TY - JOUR TI - Endogenous Levels of Alpha-Synuclein Modulate Seeding and Aggregation in Cultured Cells AU - Vasili, Eftychia AU - Dominguez-Meijide, Antonio AU - Flores-León, Manuel AU - Al-Azzani, Mohammed AU - Kanellidi, Angeliki AU - Melki, Ronald AU - Stefanis, Leonidas AU - Outeiro, Tiago Fleming T2 - Molecular Neurobiology AB - Abstract Parkinson’s disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein in intraneuronal inclusions known as Lewy bodies and Lewy neurites. Multiple studies strongly implicate the levels of alpha-synuclein as a major risk factor for the onset and progression of Parkinson’s disease. Alpha-synuclein pathology spreads progressively throughout interconnected brain regions but the precise molecular mechanisms underlying the seeding of alpha-synuclein aggregation are still unclear. Here, using stable cell lines expressing alpha-synuclein, we examined the correlation between endogenous alpha-synuclein levels and the seeding propensity by exogenous alpha-synuclein preformed fibrils. We applied biochemical approaches and imaging methods in stable cell lines expressing alpha-synuclein and in primary neurons to determine the impact of alpha-synuclein levels on seeding and aggregation. Our results indicate that the levels of alpha-synuclein define the pattern and severity of aggregation and the extent of p-alpha-synuclein deposition, likely explaining the selective vulnerability of different cell types in synucleinopathies. The elucidation of the cellular processes involved in the pathological aggregation of alpha-synuclein will enable the identification of novel targets and the development of therapeutic strategies for Parkinson’s disease and other synucleinopathies. DA - 2022/02// PY - 2022 DO - 10.1007/s12035-021-02713-2 DP - DOI.org (Crossref) VL - 59 IS - 2 SP - 1273 EP - 1284 J2 - Mol Neurobiol LA - en SN - 0893-7648, 1559-1182 UR - https://link.springer.com/10.1007/s12035-021-02713-2 Y2 - 2022/04/13/06:48:04 KW - peer-reviewed ER - TY - JOUR TI - CSF p-tau increase in response to Aβ-type and Danish-type cerebral amyloidosis and in the absence of neurofibrillary tangles AU - Kaeser, Stephan A. AU - Häsler, Lisa M. AU - Lambert, Marius AU - Bergmann, Carina AU - Bottelbergs, Astrid AU - Theunis, Clara AU - Mercken, Marc AU - Jucker, Mathias T2 - Acta Neuropathologica DA - 2021/12/28/ PY - 2021 DO - 10.1007/s00401-021-02400-5 DP - DOI.org (Crossref) J2 - Acta Neuropathol LA - en SN - 0001-6322, 1432-0533 UR - https://link.springer.com/10.1007/s00401-021-02400-5 AN - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742811/ DB - PMC Y2 - 2022/01/03/22:04:58 KW - peer-reviewed ER - TY - JOUR TI - Structures of α-synuclein filaments from multiple system atrophy AU - Schweighauser, Manuel AU - Shi, Yang AU - Tarutani, Airi AU - Kametani, Fuyuki AU - Murzin, Alexey G. AU - Ghetti, Bernardino AU - Matsubara, Tomoyasu AU - Tomita, Taisuke AU - Ando, Takashi AU - Hasegawa, Kazuko AU - Murayama, Shigeo AU - Yoshida, Mari AU - Hasegawa, Masato AU - Scheres, Sjors H. W. AU - Goedert, Michel T2 - Nature DA - 2020/09/17/ PY - 2020 DO - 10.1038/s41586-020-2317-6 DP - DOI.org (Crossref) VL - 585 IS - 7825 SP - 464 EP - 469 J2 - Nature LA - en SN - 0028-0836, 1476-4687 UR - http://www.nature.com/articles/s41586-020-2317-6 AN - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116528/ DB - PMC Y2 - 2021/02/24/21:48:24 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models AU - Mavroeidi, Panagiota AU - Arvanitaki, Fedra AU - Karakitsou, Anastasia-Kiriaki AU - Vetsi, Maria AU - Kloukina, Ismini AU - Zweckstetter, Markus AU - Giller, Karin AU - Becker, Stefan AU - Sorrentino, Zachary A. AU - Giasson, Benoit I. AU - Jensen, Poul Henning AU - Stefanis, Leonidas AU - Xilouri, Maria T2 - Acta Neuropathologica DA - 2019/09// PY - 2019 DO - 10.1007/s00401-019-02014-y DP - DOI.org (Crossref) VL - 138 IS - 3 SP - 415 EP - 441 J2 - Acta Neuropathol LA - en SN - 0001-6322, 1432-0533 UR - http://link.springer.com/10.1007/s00401-019-02014-y AN - https://pubmed.ncbi.nlm.nih.gov/31011860/ DB - PMC Y2 - 2021/03/26/20:20:46 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Structures of filaments from Pick’s disease reveal a novel tau protein fold AU - Falcon, Benjamin AU - Zhang, Wenjuan AU - Murzin, Alexey G. AU - Murshudov, Garib AU - Garringer, Holly J. AU - Vidal, Ruben AU - Crowther, R. Anthony AU - Ghetti, Bernardino AU - Scheres, Sjors H. W. AU - Goedert, Michel T2 - Nature DA - 2018/09// PY - 2018 DO - 10.1038/s41586-018-0454-y DP - Crossref VL - 561 IS - 7721 SP - 137 EP - 140 LA - en SN - 0028-0836, 1476-4687 UR - http://www.nature.com/articles/s41586-018-0454-y AN - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204212/ DB - PMC Y2 - 2018/12/11/14:47:25 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Similar neuronal imprint and no cross-seeded fibrils in α-synuclein aggregates from MSA and Parkinson’s disease AU - Laferrière, Florent AU - Claverol, Stéphane AU - Bezard, Erwan AU - De Giorgi, Francesca AU - Ichas, François T2 - npj Parkinson's Disease AB - Abstract Aggregated alpha-synuclein (α-syn) is a principal constituent of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) observed respectively inside neurons in Parkinson’s disease (PD) and oligodendrocytes in multiple system atrophy (MSA). Yet, the cellular origin, the pathophysiological role, and the mechanism of formation of these inclusions bodies (IBs) remain to be elucidated. It has recently been proposed that α-syn IBs eventually cause the demise of the host cell by virtue of the cumulative sequestration of partner proteins and organelles. In particular, the hypothesis of a local cross-seeding of other fibrillization-prone proteins like tau or TDP-43 has also been put forward. We submitted sarkosyl-insoluble extracts of post-mortem brain tissue from PD, MSA and control subjects to a comparative proteomic analysis to address these points. Our studies indicate that: (i) α-syn is by far the most enriched protein in PD and MSA extracts compared to controls; (ii) PD and MSA extracts share a striking overlap of their sarkosyl-insoluble proteomes, consisting of a vast majority of mitochondrial and neuronal synaptic proteins, and (iii) other fibrillization-prone protein candidates possibly cross-seeded by α-syn are neither found in PD nor MSA extracts. Thus, our results (i) support the idea that pre-assembled building blocks originating in neurons serve to the formation of GCIs in MSA, (ii) show no sign of amyloid cross-seeding in either synucleinopathy, and (iii) point to the sequestration of mitochondria and of neuronal synaptic components in both LBs and GCIs. DA - 2022/12// PY - 2022 DO - 10.1038/s41531-021-00264-w DP - DOI.org (Crossref) VL - 8 IS - 1 SP - 10 J2 - npj Parkinsons Dis. LA - en SN - 2373-8057 UR - https://www.nature.com/articles/s41531-021-00264-w AN - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758785/ DB - PMC Y2 - 2022/02/09/13:52:24 KW - peer-reviewed ER - TY - JOUR TI - Overexpression of α-Synuclein by Oligodendrocytes in Transgenic Mice Does Not Recapitulate the Fibrillar Aggregation Seen in Multiple System Atrophy AU - Laferrière, Florent AU - He, Xin AU - Zinghirino, Federica AU - Doudnikoff, Evelyne AU - Faggiani, Emilie AU - Meissner, Wassilios G. AU - Bezard, Erwan AU - De Giorgi, Francesca AU - Ichas, François T2 - Cells AB - The synucleinopathy underlying multiple system atrophy (MSA) is characterized by the presence of abundant amyloid inclusions containing fibrillar α-synuclein (α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinson’s disease (PD) where the pathological α-syn aggregates are almost exclusively neuronal, the α-syn inclusions in MSA are principally observed in oligodendrocytes (OLs) where they form glial cytoplasmic inclusions (GCIs). This is intriguing because differentiated OLs express low levels of α-syn, yet pathogenic amyloid α-syn seeds require significant amounts of α-syn monomers to feed their fibrillar growth and to eventually cause the buildup of cytopathological inclusions. One of the transgenic mouse models of this disease is based on the targeted overexpression of human α-syn in OLs using the PLP promoter. In these mice, the histopathological images showing a rapid emergence of S129-phosphorylated α-syn inside OLs are considered as equivalent to GCIs. Instead, we report here that they correspond to the accumulation of phosphorylated α-syn monomers/oligomers and not to the appearance of the distinctive fibrillar α-syn aggregates that are present in the brains of MSA or PD patients. In spite of a propensity to co-sediment with myelin sheath contaminants, the phosphorylated forms found in the brains of the transgenic animals are soluble (>80%). In clear contrast, the phosphorylated species present in the brains of MSA and PD patients are insoluble fibrils (>95%). Using primary cultures of OLs from PLP-αSyn mice we observed a variable association of S129-phosphorylated α-syn with the cytoplasmic compartment, the nucleus and with membrane domains suggesting that OLs functionally accommodate the phospho-α-syn deriving from experimental overexpression. Yet and while not taking place spontaneously, fibrillization can be seeded in these primary cultures by challenging the OLs with α-syn preformed fibrils (PFFs). This indicates that a targeted overexpression of α-syn does not model GCIs in mice but that it can provide a basis for seeding aggregation using PFFs. This approach could help establishing a link between α-syn aggregation and the development of a clinical phenotype in these transgenic animals. DA - 2020/11// PY - 2020 DO - 10.3390/cells9112371 DP - www.mdpi.com VL - 9 IS - 11 SP - 2371 LA - en PB - Multidisciplinary Digital Publishing Institute UR - https://www.mdpi.com/2073-4409/9/11/2371 AN - mdpi Y2 - 2021/01/13/18:19:57 KW - GCIs KW - multiple system atrophy KW - peer-reviewed KW - α-synuclein ER - TY - JOUR TI - Novel tau filament fold in corticobasal degeneration AU - Zhang, Wenjuan AU - Tarutani, Airi AU - Newell, Kathy L. AU - Murzin, Alexey G. AU - Matsubara, Tomoyasu AU - Falcon, Benjamin AU - Vidal, Ruben AU - Garringer, Holly J. AU - Shi, Yang AU - Ikeuchi, Takeshi AU - Murayama, Shigeo AU - Ghetti, Bernardino AU - Hasegawa, Masato AU - Goedert, Michel AU - Scheres, Sjors H. W. T2 - Nature DA - 2020/04/09/ PY - 2020 DO - 10.1038/s41586-020-2043-0 DP - DOI.org (Crossref) VL - 580 IS - 7802 SP - 283 EP - 287 J2 - Nature LA - en SN - 0028-0836, 1476-4687 UR - http://www.nature.com/articles/s41586-020-2043-0 AN - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148158/ DB - PMC Y2 - 2022/03/07/15:48:17 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules AU - Falcon, Benjamin AU - Zivanov, Jasenko AU - Zhang, Wenjuan AU - Murzin, Alexey G. AU - Garringer, Holly J. AU - Vidal, Ruben AU - Crowther, R. Anthony AU - Newell, Kathy L. AU - Ghetti, Bernardino AU - Goedert, Michel AU - Scheres, Sjors H.W. T2 - Nature AB - Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers–, CTE has since been identified in former participants of other contact sports, ex-military personnel and following physical abuse–. No disease-modifying therapies exist and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels,. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer’s disease and other tauopathies,. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. We used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments, with resolutions down to 2.3 Å, from the brains of three individuals with CTE, one American football player and two boxers. We show that filament structures are identical in the three cases, but distinct from those of Alzheimer’s and Pick’s diseases, and from those formed in vitro–. Like in Alzheimer's disease,,–, all six brain tau isoforms assemble into CTE filaments, and residues K274/S305-R379 form the ordered core of two identical C-shaped protofilaments. However, CTE filaments have novel protofilament interfaces, resulting in different overall morphologies. Moreover, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from Alzheimer's disease brain. This cavity encloses an additional density that is not connected to tau, suggesting that incorporation of cofactors may play a role in tau aggregation in CTE. The tau filament structures presented here provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases. DA - 2019/04// PY - 2019 DO - 10.1038/s41586-019-1026-5 DP - PubMed Central VL - 568 IS - 7752 SP - 420 EP - 423 J2 - Nature SN - 0028-0836 UR - https://www.nature.com/articles/s41586-019-1026-5 AN - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472968/ DB - PMC Y2 - 2020/04/21/17:37:33 KW - peer-reviewed ER - TY - JOUR TI - Les protéinopathies infectieuses de Parkinson et d’Alzheimer AU - Melki, R. T2 - Bulletin de l'Académie Nationale de Médecine DA - 2020/03// PY - 2020 DO - 10.1016/j.banm.2019.12.019 DP - DOI.org (Crossref) VL - 204 IS - 3 SP - 224 EP - 231 J2 - Bulletin de l'Académie Nationale de Médecine LA - fr SN - 00014079 UR - https://linkinghub.elsevier.com/retrieve/pii/S0001407920300182 AN - https://hal-cea.archives-ouvertes.fr/cea-02859853 DB - hal-cea Y2 - 2021/03/25/18:37:54 KW - peer-reviewed ER - TY - JOUR TI - LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies AU - Emmenegger, Marc AU - De Cecco, Elena AU - Hruska‐Plochan, Marian AU - Eninger, Timo AU - Schneider, Matthias M AU - Barth, Melanie AU - Tantardini, Elena AU - de Rossi, Pierre AU - Bacioglu, Mehtap AU - Langston, Rebekah G AU - Kaganovich, Alice AU - Bengoa‐Vergniory, Nora AU - Gonzalez‐Guerra, Andrès AU - Avar, Merve AU - Heinzer, Daniel AU - Reimann, Regina AU - Häsler, Lisa M AU - Herling, Therese W AU - Matharu, Naunehal S AU - Landeck, Natalie AU - Luk, Kelvin AU - Melki, Ronald AU - Kahle, Philipp J AU - Hornemann, Simone AU - Knowles, Tuomas P J AU - Cookson, Mark R AU - Polymenidou, Magdalini AU - Jucker, Mathias AU - Aguzzi, Adriano T2 - EMBO Molecular Medicine DA - 2021/09/07/ PY - 2021 DO - 10.15252/emmm.202114745 DP - DOI.org (Crossref) VL - 13 IS - 9 J2 - EMBO Mol Med LA - en SN - 1757-4676, 1757-4684 UR - https://onlinelibrary.wiley.com/doi/10.15252/emmm.202114745 AN - https://www.repository.cam.ac.uk/handle/1810/328508 DB - https://www.repository.cam.ac.uk/handle/1810/328508 Y2 - 2022/02/09/13:39:31 KW - peer-reviewed ER - TY - JOUR TI - Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases AU - Zhang, Wenjuan AU - Falcon, Benjamin AU - Murzin, Alexey G AU - Fan, Juan AU - Crowther, R Anthony AU - Goedert, Michel AU - Scheres, Sjors HW T2 - eLife AB - Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer’s and Pick’s diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structures of three types reveal similar ‘kinked hairpin’ folds, in which the second and third repeats pack against each other. 2N3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack in a parallel manner. The heparin-induced tau filaments differ from those of Alzheimer’s or Pick’s disease, which have larger cores with different repeat compositions. Our results illustrate the structural versatility of amyloid filaments, and raise questions about the relevance of in vitro assembly. DA - 2019/02/05/ PY - 2019 DO - 10.7554/eLife.43584 DP - DOI.org (Crossref) VL - 8 SP - e43584 LA - en SN - 2050-084X UR - https://elifesciences.org/articles/43584 AN - https://www.biorxiv.org/content/10.1101/468892v1 DB - Biorxiv Y2 - 2022/03/14/16:46:06 ER - TY - JOUR TI - Distinct alpha‐Synuclein species induced by seeding are selectively cleared by the Lysosome or the Proteasome in neuronally differentiated SH‐SY5Y cells AU - Pantazopoulou, Marina AU - Brembati, Viviana AU - Kanellidi, Angeliki AU - Bousset, Luc AU - Melki, Ronald AU - Stefanis, Leonidas T2 - Journal of Neurochemistry DA - 2020/09/22/ PY - 2020 DO - 10.1111/jnc.15174 DP - DOI.org (Crossref) SP - jnc.15174 J2 - J Neurochem LA - en SN - 0022-3042, 1471-4159 UR - https://onlinelibrary.wiley.com/doi/10.1111/jnc.15174 AN - https://zenodo.org/record/4570369#.YD0kCV1KiWh DB - Zenodo Y2 - 2020/11/20/17:55:16 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Assessment of the efficacy of different procedures that remove and disassemble alpha-synuclein, tau and A-beta fibrils from laboratory material and surfaces AU - Fenyi, Alexis AU - Coens, Audrey AU - Bellande, Tracy AU - Melki, Ronald AU - Bousset, Luc T2 - Scientific Reports AB - α-synuclein fibrillar polymorphs, Tau and Aß 1-42 fibrillar assemblies have been shown to propagate, amplify and trigger the formation of protein deposits reminiscent of those present within the central nervous system of patients developing synucleinopathies, tauopathies and amyloid plaques after injection intracerebrally, intramuscularly, intraperitoneally or within the blood stream of model animals. They are thus hazardous and there is need for decontamination and inactivation procedures for laboratory surfaces and non-disposable material. We assessed the effectiveness of different reagents to clean and disassemble potentially pathogenic assemblies adsorbed on non-disposable materials in laboratories. We show that commercial detergents and SDS are way more suited to detach α-synuclein fibrillar polymorphs, Tau and Aß 1-42 fibrillar assemblies from contaminated surfaces and disassemble the fibrils than methods designed to decrease PrP prion infectivity. Our observations reveal that the choice of the most adapted cleaning procedure for one given protein assembly or fibrillar polymorph should integrate detergent's cleaning efficiency, material compatibility and capacity to dismantle assemblies. We provide an integrated representation where desorption and neutralization efficacy and surface compatibility are combined to facilitate the choice of the most adapted decontamination procedure. This representation, together with good laboratory practices, contributes to reducing potential health hazards associated to manipulating protein assemblies with prion-like properties. DA - 2018/07/17/ PY - 2018 DO - 10.1038/s41598-018-28856-2 DP - PubMed VL - 8 IS - 1 SP - 10788 J2 - Sci Rep LA - eng SN - 2045-2322 UR - https://www.nature.com/articles/s41598-018-28856-2 AN - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050226/ DB - PMC KW - peer-reviewed ER - TY - JOUR TI - Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life AU - Uhlmann, Ruth E. AU - Rother, Christine AU - Rasmussen, Jay AU - Schelle, Juliane AU - Bergmann, Carina AU - Ullrich Gavilanes, Emily M. AU - Fritschi, Sarah K. AU - Buehler, Anika AU - Baumann, Frank AU - Skodras, Angelos AU - Al-Shaana, Rawaa AU - Beschorner, Natalie AU - Ye, Lan AU - Kaeser, Stephan A. AU - Obermüller, Ulrike AU - Christensen, Søren AU - Kartberg, Fredrik AU - Stavenhagen, Jeffrey B. AU - Rahfeld, Jens-Ulrich AU - Cynis, Holger AU - Qian, Fang AU - Weinreb, Paul H. AU - Bussiere, Thierry AU - Walker, Lary C. AU - Staufenbiel, Matthias AU - Jucker, Mathias T2 - Nature Neuroscience DA - 2020/12// PY - 2020 DO - 10.1038/s41593-020-00737-w DP - DOI.org (Crossref) VL - 23 IS - 12 SP - 1580 EP - 1588 J2 - Nat Neurosci LA - en SN - 1097-6256, 1546-1726 UR - http://www.nature.com/articles/s41593-020-00737-w AN - https://zenodo.org/record/4562254#.YDfVlF1KgdW DB - Zenodo Y2 - 2021/02/25/17:37:13 KW - peer-reviewed ER - TY - JOUR TI - Clustering of Tau fibrils impairs the synaptic composition of α3‐Na+/K+‐ATPase and AMPA receptors AU - Shrivastava, Amulya Nidhi AU - Redeker, Virginie AU - Pieri, Laura AU - Bousset, Luc AU - Renner, Marianne AU - Madiona, Karine AU - Mailhes‐Hamon, Caroline AU - Coens, Audrey AU - Buée, Luc AU - Hantraye, Philippe AU - Triller, Antoine AU - Melki, Ronald T2 - The EMBO Journal AB - Tau assemblies have prion‐like properties: they propagate from one neuron to another and amplify by seeding the aggregation of endogenous Tau. Although key in prion‐like propagation, the binding of exogenous Tau assemblies to the plasma membrane of naïve neurons is not understood. We report that fibrillar Tau forms clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+/K+‐ATPase (NKA) and AMPA receptors. The consequence of the clustering is a reduction in the amount of α3‐NKA and an increase in the amount of GluA2‐AMPA receptor at synapses. Furthermore, fibrillar Tau destabilizes functional NKA complexes. Tau and α‐synuclein aggregates often co‐exist in patients’ brains. We now show evidences for cross‐talk between these pathogenic aggregates with α‐synuclein fibrils dramatically enhancing fibrillar Tau clustering and synaptic localization. Our results suggest that fibrillar α‐synuclein and Tau cross‐talk at the plasma membrane imbalance neuronal homeostasis. Synopsis Embedded Image Pathogenic fibrillar Tau remodel excitatory synaptic protein composition and imbalance neuronal homeostasis. Exogenous fibrillar‐Tau clusters at excitatory synapses.The membrane interactome of fibrillar Tau is identified.Fibrillar‐Tau interacts with Na+/K+‐ATPase and GluA2‐AMPA receptor.Fibrillar Tau reduces Na+/K+‐ATPase and increases GluA2‐AMPA receptor at synapses.Synuclein fibrils cross‐talk with fibrillar‐Tau at neuronal membrane. DA - 2019/01/08/ PY - 2019 DO - 10.15252/embj.201899871 DP - emboj.embopress.org SP - e99871 LA - en SN - 0261-4189, 1460-2075 UR - https://www.embopress.org/doi/full/10.15252/embj.201899871 Y2 - 2019/01/11/13:53:06 KW - cross‐talk of pathogenic proteins KW - highlight KW - misfolding disease KW - peer-reviewed KW - protein aggregation and clustering KW - single‐particle tracking KW - tauopathies ER - TY - JOUR TI - Cryo-EM structures of tau filaments from Alzheimer’s disease AU - Fitzpatrick, Anthony W. P. AU - Falcon, Benjamin AU - He, Shaoda AU - Murzin, Alexey G. AU - Murshudov, Garib AU - Garringer, Holly J. AU - Crowther, R. Anthony AU - Ghetti, Bernardino AU - Goedert, Michel AU - Scheres, Sjors H. W. T2 - Nature DA - 2017/07/05/ PY - 2017 DO - 10.1038/nature23002 DP - Crossref VL - 547 IS - 7662 SP - 185 EP - 190 SN - 0028-0836, 1476-4687 UR - http://www.nature.com/doifinder/10.1038/nature23002 AN - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552202/ DB - PMC Y2 - 2018/11/26/16:27:04 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607 AU - Shi, Yang AU - Murzin, Alexey G. AU - Falcon, Benjamin AU - Epstein, Alexander AU - Machin, Jonathan AU - Tempest, Paul AU - Newell, Kathy L. AU - Vidal, Ruben AU - Garringer, Holly J. AU - Sahara, Naruhiko AU - Higuchi, Makoto AU - Ghetti, Bernardino AU - Jang, Ming-Kuei AU - Scheres, Sjors H. W. AU - Goedert, Michel T2 - Acta Neuropathologica AB - Abstract Tau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments. DA - 2021/05// PY - 2021 DO - 10.1007/s00401-021-02294-3 DP - DOI.org (Crossref) VL - 141 IS - 5 SP - 697 EP - 708 J2 - Acta Neuropathol LA - en SN - 0001-6322, 1432-0533 UR - https://link.springer.com/10.1007/s00401-021-02294-3 Y2 - 2022/03/09/14:50:09 ER - TY - JOUR TI - Differential Membrane Binding and Seeding of Distinct α-Synuclein Fibrillar Polymorphs AU - Shrivastava, Amulya Nidhi AU - Bousset, Luc AU - Renner, Marianne AU - Redeker, Virginie AU - Savistchenko, Jimmy AU - Triller, Antoine AU - Melki, Ronald T2 - Biophysical Journal DA - 2020/01/27/ PY - 2020 DO - 10.1016/j.bpj.2020.01.022 DP - www.cell.com VL - 118 IS - 6 SP - 1301 EP - 1320 J2 - Biophysical Journal LA - English PB - Elsevier SN - 0006-3495 UR - https://www.cell.com/biophysj/abstract/S0006-3495(20)30069-2 Y2 - 2020/03/23/17:49:28 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Structure-based classification of tauopathies AU - Shi, Yang AU - Zhang, Wenjuan AU - Yang, Yang AU - Murzin, Alexey G. AU - Falcon, Benjamin AU - Kotecha, Abhay AU - van Beers, Mike AU - Tarutani, Airi AU - Kametani, Fuyuki AU - Garringer, Holly J. AU - Vidal, Ruben AU - Hallinan, Grace I. AU - Lashley, Tammaryn AU - Saito, Yuko AU - Murayama, Shigeo AU - Yoshida, Mari AU - Tanaka, Hidetomo AU - Kakita, Akiyoshi AU - Ikeuchi, Takeshi AU - Robinson, Andrew C. AU - Mann, David M. A. AU - Kovacs, Gabor G. AU - Revesz, Tamas AU - Ghetti, Bernardino AU - Hasegawa, Masato AU - Goedert, Michel AU - Scheres, Sjors H. W. T2 - Nature DA - 2021/10/14/ PY - 2021 DO - 10.1038/s41586-021-03911-7 DP - DOI.org (Crossref) VL - 598 IS - 7880 SP - 359 EP - 363 J2 - Nature LA - en SN - 0028-0836, 1476-4687 UR - https://www.nature.com/articles/s41586-021-03911-7 Y2 - 2021/10/20/14:09:35 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Detection of alpha-synuclein aggregates in gastrointestinal biopsies by protein misfolding cyclic amplification AU - Fenyi, Alexis AU - Leclair-Visonneau, Laurène AU - Clairembault, Thomas AU - Coron, Emmanuel AU - Neunlist, Michel AU - Melki, Ronald AU - Derkinderen, Pascal AU - Bousset, Luc T2 - Neurobiology of Disease AB - Lewy bodies and neurites, the pathological signatures found in the central nervous system of Parkinson's disease (PD) patients, are primarily composed of aggregated alpha-synuclein (aSyn). The observation that aSyn aggregates are also found in the enteric nervous system has prompted several studies aimed at developing a diagnostic procedure based on the detection of pathological aSyn in gastrointestinal (GI) biopsies. The existing studies, which have all used immunohistochemistry for the detection of pathological aSyn, have had conflicting results. In the current survey, we analyzed the seeding propensity of aSyn aggregates from GI biopsies. A total of 29 subjects participated to this study, 18 PD patients and 11 controls. For each patient, 2 to 4 GI biopsies were taken from the same site (antrum, sigmoid colon or rectum) and used to seed the aggregation of recombinant aSyn in an assay inspired from the protein misfolding cyclic amplification (PMCA) method. In a subset of patients and controls (14 and 3, respectively), one or two additional biopsies were analyzed by immunohistochemistry for the presence of phosphorylated aSyn histopathology (PASH) using antibodies against phosphorylated aSyn and PGP 9.5. Except for one subject, none of the control samples seeded aSyn aggregation in PMCA reaction. GI biopsies from patients with PD seeded aSyn aggregation in 10 out of 18 cases (7 from the sigmoid colon, 2 from the antrum and one from the rectum). There was good agreement between PMCA and immunohistochemistry results as, except for two cases, all PMCA-positive PD patients were also PASH-positive. Our findings show that the PMCA method we implemented is capable of detecting aSyn aggregates in routine GI biopsies. They also suggest that rectum biopsies do not contain sufficient amounts of aggregated aSyn to detect seeded assembly by PMCA. While encouraging, our findings indicate that further studies are needed to establish the diagnostic potential of the PMCA method we implemented to detect aSyn aggregates in upper GI biopsies. DA - 2019/09/01/ PY - 2019 DO - 10.1016/j.nbd.2019.05.002 DP - ScienceDirect VL - 129 SP - 38 EP - 43 J2 - Neurobiology of Disease LA - en SN - 0969-9961 UR - http://www.sciencedirect.com/science/article/pii/S0969996119301172 Y2 - 2019/12/02/16:51:30 KW - Alpha-synuclein KW - Biopsy KW - Enteric nervous system KW - Gut KW - Parkinson's disease KW - Protein misfolding cyclic amplification KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy AU - Guerrero-Ferreira, Ricardo AU - Taylor, Nicholas MI AU - Arteni, Ana-Andreea AU - Kumari, Pratibha AU - Mona, Daniel AU - Ringler, Philippe AU - Britschgi, Markus AU - Lauer, Matthias E AU - Makky, Ali AU - Verasdonck, Joeri AU - Riek, Roland AU - Melki, Ronald AU - Meier, Beat H AU - Böckmann, Anja AU - Bousset, Luc AU - Stahlberg, Henning T2 - eLife A2 - Scheres, Sjors HW AB - Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability. DA - 2019/12/09/ PY - 2019 DO - 10.7554/eLife.48907 DP - eLife VL - 8 SP - e48907 SN - 2050-084X UR - https://doi.org/10.7554/eLife.48907 Y2 - 2019/12/10/15:09:45 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies AU - Van der Perren, Anke AU - Gelders, Géraldine AU - Fenyi, Alexis AU - Bousset, Luc AU - Brito, Filipa AU - Peelaerts, Wouter AU - Van den Haute, Chris AU - Gentleman, Steve AU - Melki, Ronald AU - Baekelandt, Veerle T2 - Acta Neuropathologica AB - Synucleinopathies, such as Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains. DA - 2020/06/01/ PY - 2020 DO - 10.1007/s00401-020-02157-3 DP - Springer Link VL - 139 IS - 6 SP - 977 EP - 1000 J2 - Acta Neuropathol LA - en SN - 1432-0533 UR - https://doi.org/10.1007/s00401-020-02157-3 Y2 - 2020/06/02/18:14:42 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions AU - Tanriöver, Gaye AU - Bacioglu, Mehtap AU - Schweighauser, Manuel AU - Mahler, Jasmin AU - Wegenast-Braun, Bettina M. AU - Skodras, Angelos AU - Obermüller, Ulrike AU - Barth, Melanie AU - Kronenberg-Versteeg, Deborah AU - Nilsson, K. Peter R. AU - Shimshek, Derya R. AU - Kahle, Philipp J. AU - Eisele, Yvonne S. AU - Jucker, Mathias T2 - Acta Neuropathologica Communications AB - Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human α-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of α-synucleinopathy bears importance for mechanistic and preclinical-translational studies. DA - 2020/08/12/ PY - 2020 DO - 10.1186/s40478-020-00993-8 DP - BioMed Central VL - 8 IS - 1 SP - 133 J2 - Acta Neuropathologica Communications SN - 2051-5960 UR - https://doi.org/10.1186/s40478-020-00993-8 Y2 - 2020/08/17/12:33:06 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization AU - Dominguez-Meijide, Antonio AU - Vasili, Eftychia AU - König, Annekatrin AU - Cima-Omori, Maria-Sol AU - Ibáñez de Opakua, Alain AU - Leonov, Andrei AU - Ryazanov, Sergey AU - Zweckstetter, Markus AU - Griesinger, Christian AU - Outeiro, Tiago F. T2 - Scientific Reports DA - 2020/12// PY - 2020 DO - 10.1038/s41598-020-69744-y DP - DOI.org (Crossref) VL - 10 IS - 1 SP - 12827 J2 - Sci Rep LA - en SN - 2045-2322 UR - http://www.nature.com/articles/s41598-020-69744-y Y2 - 2021/02/24/20:49:00 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Novel self-replicating α-synuclein polymorphs that escape ThT monitoring can spontaneously emerge and acutely spread in neurons AU - De Giorgi, Francesca AU - Laferrière, Florent AU - Zinghirino, Federica AU - Faggiani, Emilie AU - Lends, Alons AU - Bertoni, Mathilde AU - Yu, Xuan AU - Grélard, Axelle AU - Morvan, Estelle AU - Habenstein, Birgit AU - Dutheil, Nathalie AU - Doudnikoff, Evelyne AU - Daniel, Jonathan AU - Claverol, Stéphane AU - Qin, Chuan AU - Loquet, Antoine AU - Bezard, Erwan AU - Ichas, François T2 - Science Advances AB - The conformational strain diversity characterizing α-synuclein (α-syn) amyloid fibrils is thought to determine the different clinical presentations of neurodegenerative diseases underpinned by a synucleinopathy. Experimentally, various α-syn fibril polymorphs have been obtained from distinct fibrillization conditions by altering the medium constituents and were selected by amyloid monitoring using the probe thioflavin T (ThT). We report that, concurrent with classical ThT-positive products, fibrillization in saline also gives rise to polymorphs invisible to ThT (τ − ). The generation of τ − fibril polymorphs is stochastic and can skew the apparent fibrillization kinetics revealed by ThT. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. They present a yet undescribed atomic organization and show an exacerbated propensity toward self-replication in cortical neurons, and in living mice, their injection into the substantia nigra pars compacta triggers a synucleinopathy that spreads toward the dorsal striatum, the nucleus accumbens, and the insular cortex. DA - 2020/10// PY - 2020 DO - 10.1126/sciadv.abc4364 DP - DOI.org (Crossref) VL - 6 IS - 40 SP - eabc4364 J2 - Sci. Adv. LA - en SN - 2375-2548 UR - https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abc4364 Y2 - 2021/02/24/20:57:34 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for Parkinson’s Disease AU - Fenyi, Alexis AU - Duyckaerts, Charles AU - Bousset, Luc AU - Braak, Heiko AU - Tredici, Kelly Del AU - Melki, Ronald AU - Neuro-CEB Neuropathology Network, on behalf of the Brainbank T2 - Cells AB - We investigated α-synuclein’s (αSyn) seeding activity in tissue from the brain and enteric nervous system. Specifically, we assessed the seeding propensity of pathogenic αSyn in formalin-fixed tissue from the gastric cardia and five brain regions of 29 individuals (12 Parkinson’s disease, 8 incidental Lewy body disease, 9 controls) using a protein misfolding cyclic amplification assay. The structural characteristics of the resultant αSyn assemblies were determined by limited proteolysis and transmission electron microscopy. We show that fixed tissue from Parkinson’s disease (PD) and incidental Lewy body disease (ILBD) seeds the aggregation of monomeric αSyn into fibrillar assemblies. Significant variations in the characteristics of fibrillar assemblies derived from different regions even within the same individual were observed. This finding suggests that fixation stabilizes seeds with an otherwise limited seeding propensity, that yield assemblies with different intrinsic structures (i.e., strains). The lag phase preceding fibril assembly for patients ≥80 was significantly shorter than in other age groups, suggesting the existence of increased numbers of seeds or a higher seeding potential of pathogenic αSyn with time. Seeding activity did not diminish in late-stage disease. No statistically significant difference in the seeding efficiency of specific regions was found, nor was there a relationship between seeding efficiency and the load of pathogenic αSyn in a particular region at a given neuropathological stage. DA - 2021/01/12/ PY - 2021 DO - 10.3390/cells10010139 DP - DOI.org (Crossref) VL - 10 IS - 1 SP - 139 J2 - Cells LA - en SN - 2073-4409 UR - https://www.mdpi.com/2073-4409/10/1/139 Y2 - 2021/03/25/18:44:15 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Tau assemblies do not behave like independently acting prion-like particles in mouse neural tissue AU - Miller, Lauren V. C. AU - Mukadam, Aamir S. AU - Durrant, Claire S. AU - Vaysburd, Marina J. AU - Katsinelos, Taxiarchis AU - Tuck, Benjamin J. AU - Sanford, Sophie AU - Sheppard, Olivia AU - Knox, Claire AU - Cheng, Shi AU - James, Leo C. AU - Coleman, Michael P. AU - McEwan, William A. T2 - Acta Neuropathologica Communications AB - Abstract A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result of collective action. Assemblies of the protein tau can exhibit seeding behaviour, potentially underlying the apparent spread of tau aggregation in many neurodegenerative diseases. Here we ask whether tau assemblies share with classical pathogens the characteristic of particulate behaviour. We used organotypic hippocampal slice cultures from P301S tau transgenic mice in order to precisely control the concentration of extracellular tau assemblies in neural tissue. Whilst untreated slices displayed no overt signs of pathology, exposure to recombinant tau assemblies could result in the formation of intraneuronal, hyperphosphorylated tau structures. However, seeding ability of tau assemblies did not titrate in a one-hit manner in neural tissue. The results suggest that seeding behaviour of tau arises at high concentrations, with implications for the interpretation of high-dose intracranial challenge experiments and the possible contribution of seeded aggregation to human disease. DA - 2021/12// PY - 2021 DO - 10.1186/s40478-021-01141-6 DP - DOI.org (Crossref) VL - 9 IS - 1 SP - 41 J2 - acta neuropathol commun LA - en SN - 2051-5960 UR - https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01141-6 Y2 - 2021/03/25/12:45:09 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons AU - Tanudjojo, Benedict AU - Shaikh, Samiha S. AU - Fenyi, Alexis AU - Bousset, Luc AU - Agarwal, Devika AU - Marsh, Jade AU - Zois, Christos AU - Heman-Ackah, Sabrina AU - Fischer, Roman AU - Sims, David AU - Melki, Ronald AU - Tofaris, George K. T2 - Nature Communications AB - Abstract α-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons. DA - 2021/12// PY - 2021 DO - 10.1038/s41467-021-23682-z DP - DOI.org (Crossref) VL - 12 IS - 1 SP - 3817 J2 - Nat Commun LA - en SN - 2041-1723 UR - http://www.nature.com/articles/s41467-021-23682-z Y2 - 2021/06/22/14:49:03 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures AU - Barth, Melanie AU - Bacioglu, Mehtap AU - Schwarz, Niklas AU - Novotny, Renata AU - Brandes, Janine AU - Welzer, Marc AU - Mazzitelli, Sonia AU - Häsler, Lisa M. AU - Schweighauser, Manuel AU - Wuttke, Thomas V. AU - Kronenberg-Versteeg, Deborah AU - Fog, Karina AU - Ambjørn, Malene AU - Alik, Ania AU - Melki, Ronald AU - Kahle, Philipp J. AU - Shimshek, Derya R. AU - Koch, Henner AU - Jucker, Mathias AU - Tanriöver, Gaye T2 - Molecular Neurodegeneration AB - Abstract Background Proteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression. Methods Alpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed. Results To study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2–3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture’s genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-year-old donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions. Conclusion The successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments. DA - 2021/12// PY - 2021 DO - 10.1186/s13024-021-00471-2 DP - DOI.org (Crossref) VL - 16 IS - 1 SP - 54 J2 - Mol Neurodegeneration LA - en SN - 1750-1326 UR - https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00471-2 Y2 - 2021/09/07/09:34:30 KW - highlight KW - peer-reviewed ER - TY - JOUR TI - Tau in the brain interstitial fluid is fragmented and seeding–competent AU - Barini, Erica AU - Plotzky, Gudrun AU - Mordashova, Yulia AU - Hoppe, Jonas AU - Rodriguez-Correa, Esther AU - Julier, Sonja AU - LePrieult, Florie AU - Mairhofer, Ina AU - Mezler, Mario AU - Biesinger, Sandra AU - Cik, Miroslav AU - Meinhardt, Marcus W. AU - Ercan-Herbst, Ebru AU - Ehrnhoefer, Dagmar E. AU - Striebinger, Andreas AU - Bodie, Karen AU - Klein, Corinna AU - Gasparini, Laura AU - Schlegel, Kerstin T2 - Neurobiology of Aging DA - 2022/01// PY - 2022 DO - 10.1016/j.neurobiolaging.2021.09.013 DP - DOI.org (Crossref) VL - 109 SP - 64 EP - 77 J2 - Neurobiology of Aging LA - en SN - 01974580 UR - https://linkinghub.elsevier.com/retrieve/pii/S0197458021002943 Y2 - 2022/02/17/17:30:15 ER - TY - RPRT TI - α-Synuclein strains influence multiple system atrophy via central and peripheral mechanisms AU - Torre Murazabal, T. AU - Van der Perren, A. AU - Coens, A. AU - Barber Janer, A. AU - Camacho-Garcia, S. AU - Stefanova, N. AU - Melki, R. AU - Baekelandt, V. AU - Peelaerts, W. AB - Abstract Multiple system atrophy (MSA) is a progressive neurodegenerative disease with prominent autonomic and motor features. Different disease subtypes are distinguished by their predominant parkinsonian or cerebellar signs. The pathognomonic feature of MSA is the presence of α-synuclein (αSyn) protein deposits in glial cells of the central and peripheral nervous system. It is unclear why MSA, that invariably presents with αSyn pathology, is clinically so heterogeneous, why it progresses at varying rates and how neuroinflammation affects disease progression. Recently, it was shown that different strains of αSyn can assemble in unique disease environments but also that a variety of strains might exist in the brain of MSA patients. We therefore investigated if different αSyn strains might influence MSA disease progression. To this aim, we injected two recombinant strains of αSyn in MSA transgenic mice and found that they significantly impact MSA disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo . By injecting αSyn strains in MSA mice we could more closely mimic a comprehensive MSA phenotype in an experimental setting. This study therefore shows that i) MSA phenotype is governed by both the αSyn strain nature and the host environment and ii) αSyn strains can directly trigger a detrimental immune response related to disease progression in MSA. DA - 2020/10/16/ PY - 2020 DO - 10.1101/2020.10.16.342089 DP - DOI.org (Crossref) LA - en M3 - preprint PB - Neuroscience UR - https://biorxiv.org/lookup/doi/10.1101/2020.10.16.342089 Y2 - 2022/02/17/14:01:24 KW - preprint ER - TY - RPRT TI - Tau assemblies enter the cytosol in a cholesterol sensitive process essential to seeded aggregation AU - Tuck, Benjamin J. AU - Miller, Lauren V. C. AU - Wilson, Emma L. AU - Katsinelos, Taxiarchis AU - Cheng, Shi AU - Vaysburd, Marina AU - Knox, Claire AU - Tredgett, Lucy AU - Metzakopian, Emmanouil AU - James, Leo C. AU - McEwan, William A. AB - Abstract Accumulating evidence supports a prion-like mechanism in the spread of assembled tau in neurodegenerative diseases. Prion-like spread is proposed to require the transit of tau assemblies to the interior of neurons in order to seed aggregation of native, cytosolic tau. This process is poorly understood and remains largely hypothetical. Here, we develop sensitive techniques to quantify the cytosolic entry of tau in real-time. We find that tau does not promote its own entry but, rather, is wholly dependent on cellular machinery. We find that entry to the widely used reporter cell line HEK293 requires clathrin whereas entry to neurons does not. Cholesterol depletion or knockdown of cholesterol transport protein Niemann-Pick type C1 in neurons renders cells highly vulnerable to cytosolic entry and seeded aggregation. Our findings establish entry as the rate-limiting step in seeded aggregation and demonstrate that dysregulated cholesterol, a feature of several neurodegenerative diseases, potentiates tau aggregation. Graphical Abstract DA - 2021/06/22/ PY - 2021 DO - 10.1101/2021.06.21.449238 DP - DOI.org (Crossref) LA - en M3 - preprint PB - Cell Biology UR - https://biorxiv.org/lookup/doi/10.1101/2021.06.21.449238 Y2 - 2022/02/17/14:02:21 KW - preprint ER - TY - RPRT TI - Cryo-EM structure of alpha-synuclein fibrils amplified by PMCA from PD and MSA patient brains AU - Burger, Domenic AU - Fenyi, Alexis AU - Bousset, Luc AU - Stahlberg, Henning AU - Melki, Ronald AB - Abstract Synucleinopathies are neurodegenerative diseases related to the aggregation of the protein alpha-synuclein (aSyn). Among these diseases, Parkinson’s disease (PD) and multiple system atrophy (MSA) are most prevalent. aSyn can readily form different fibrillar polymorphs, if exposed to an air-water interface or by templating with pre-existing fibrils. We here report the structures of three fibrillar polymorphs that were obtained after seeding monomeric aSyn with PD and MSA patients brain homogenates using protein misfolding cyclic amplification (PMCA). Seeding with a control brain homogenate did not produce fibrils, and seeding with other in vitro generated fibrillar polymorphs as a control faithfully produced polymorphs of a different type. The here determined fibril structures from PD and MSA brain tissue represent new folds, which partly resemble that of previously reported in vitro generated fibrils from Y39 phosphorylated aSyn protein. The relevance of these fibrils for synucleinopathies in humans remains to be further investigated. Impact Statement Neurodegenerative diseases such as Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are suspected to be causatively related to the prion-like propagation of aggregates of the protein alpha-synuclein (aSyn). The fibril structures reported here were obtained after seeding from diseased human brain homogenate and differ from all previously published aSyn fibril arrangements. In case these fibrils would turn out to be the long sought causative agents of these diseases, their structures might lead to the development of therapeutic strategies to modify these diseases and to a better understanding of the mechanistic processes that lead to neurodegeneration and spreading of the diseases. DA - 2021/07/09/ PY - 2021 DO - 10.1101/2021.07.08.451588 DP - DOI.org (Crossref) LA - en M3 - preprint PB - Neuroscience UR - https://biorxiv.org/lookup/doi/10.1101/2021.07.08.451588 Y2 - 2022/02/17/14:00:32 KW - preprint ER - TY - JOUR TI - Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts AU - Teil, Margaux AU - Arotcarena, Marie-Laure AU - Faggiani, Emilie AU - Laferriere, Florent AU - Bezard, Erwan AU - Dehay, Benjamin T2 - Biomolecules AB - Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time. DA - 2020/03/03/ PY - 2020 DO - 10.3390/biom10030391 DP - DOI.org (Crossref) VL - 10 IS - 3 SP - 391 J2 - Biomolecules LA - en SN - 2218-273X ST - Targeting α-Synuclein for PD Therapeutics UR - https://www.mdpi.com/2218-273X/10/3/391 Y2 - 2022/02/14/16:47:12 KW - peer-reviewed ER - TY - JOUR TI - Increased Immune Activation by Pathologic α‐Synuclein in Parkinson's Disease AU - Grozdanov, Veselin AU - Bousset, Luc AU - Hoffmeister, Meike AU - Bliederhaeuser, Corinna AU - Meier, Christoph AU - Madiona, Karine AU - Pieri, Laura AU - Kiechle, Martin AU - McLean, Pamela J. AU - Kassubek, Jan AU - Behrends, Christian AU - Ludolph, Albert C. AU - Weishaupt, Jochen H. AU - Melki, Ronald AU - Danzer, Karin M. T2 - Annals of Neurology DA - 2019/10// PY - 2019 DO - 10.1002/ana.25557 DP - DOI.org (Crossref) VL - 86 IS - 4 SP - 593 EP - 606 J2 - Ann Neurol LA - en SN - 0364-5134, 1531-8249 UR - https://onlinelibrary.wiley.com/doi/10.1002/ana.25557 DB - https://oparu.uni-ulm.de/xmlui/handle/123456789/38929 Y2 - 2022/02/14/17:47:10 KW - peer-reviewed ER - TY - JOUR TI - Convergent molecular defects underpin diverse neurodegenerative diseases AU - Tofaris, George K AU - Buckley, Noel J T2 - Journal of Neurology, Neurosurgery & Psychiatry AB - In our ageing population, neurodegenerative disorders carry an enormous personal, societal and economic burden. Although neurodegenerative diseases are often thought of as clinicopathological entities, increasing evidence suggests a considerable overlap in the molecular underpinnings of their pathogenesis. Such overlapping biological processes include the handling of misfolded proteins, defective organelle trafficking, RNA processing, synaptic health and neuroinflammation. Collectively but in different proportions, these biological processes in neurons or non-neuronal cells lead to regionally distinct patterns of neuronal vulnerability and progression of pathology that could explain the disease symptomology. With the advent of patient-derived cellular models and novel genetic manipulation tools, we are now able to interrogate this commonality despite the cellular complexity of the brain in order to develop novel therapeutic strategies to prevent or arrest neurodegeneration. Here, we describe broadly these concepts and their relevance across neurodegenerative diseases. DA - 2018/09// PY - 2018 DO - 10.1136/jnnp-2017-316988 DP - DOI.org (Crossref) VL - 89 IS - 9 SP - 962 EP - 969 J2 - J Neurol Neurosurg Psychiatry LA - en SN - 0022-3050, 1468-330X UR - https://jnnp.bmj.com/lookup/doi/10.1136/jnnp-2017-316988 Y2 - 2022/02/14/17:10:02 KW - peer-reviewed ER - TY - JOUR TI - Synthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models AU - McMurray, Lindsay AU - Macdonald, Jennifer A. AU - Ramakrishnan, Nisha Kuzhuppilly AU - Zhao, Yanyan AU - Williamson, David W. AU - Tietz, Ole AU - Zhou, Xiaoyun AU - Kealey, Steven AU - Fagan, Steven G. AU - Smolek, Tomáš AU - Cubinkova, Veronika AU - Žilka, Norbert AU - Spillantini, Maria Grazia AU - Tolkovsky, Aviva M. AU - Goedert, Michel AU - Aigbirhio, Franklin I. T2 - ACS Chemical Neuroscience DA - 2021/06/02/ PY - 2021 DO - 10.1021/acschemneuro.0c00790 DP - DOI.org (Crossref) VL - 12 IS - 11 SP - 1885 EP - 1893 J2 - ACS Chem. Neurosci. LA - en SN - 1948-7193, 1948-7193 UR - https://pubs.acs.org/doi/10.1021/acschemneuro.0c00790 Y2 - 2022/01/03/22:05:34 KW - peer-reviewed ER - TY - JOUR TI - Identification of cis-acting determinants mediating the unconventional secretion of tau AU - Katsinelos, Taxiarchis AU - McEwan, William A. AU - Jahn, Thomas R. AU - Nickel, Walter T2 - Scientific Reports AB - Abstract The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer’s disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P 2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis -elements that are important for both unconventional secretion and trans-cellular propagation of tau. DA - 2021/12// PY - 2021 DO - 10.1038/s41598-021-92433-3 DP - DOI.org (Crossref) VL - 11 IS - 1 SP - 12946 J2 - Sci Rep LA - en SN - 2045-2322 UR - http://www.nature.com/articles/s41598-021-92433-3 Y2 - 2021/06/22/14:50:37 KW - peer-reviewed ER - TY - JOUR TI - The differential solvent exposure of N-terminal residues provides ‘fingerprints’ of alpha-synuclein fibrillar polymorphs AU - Landureau, Maud AU - Redeker, Virginie AU - Bellande, Tracy AU - Eyquem, Stéphanie AU - Melki, Ronald T2 - Journal of Biological Chemistry DA - 2021/04// PY - 2021 DO - 10.1016/j.jbc.2021.100737 DP - DOI.org (Crossref) SP - 100737 J2 - Journal of Biological Chemistry LA - en SN - 00219258 UR - https://linkinghub.elsevier.com/retrieve/pii/S0021925821005263 Y2 - 2021/05/05/12:57:53 KW - peer-reviewed ER - TY - JOUR TI - Reduced serum immunoglobulin G concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course AU - Zoehner, Greta AU - Miclea, Andrei AU - Salmen, Anke AU - Kamber, Nicole AU - Diem, Lara AU - Friedli, Christoph AU - Bagnoud, Maud AU - Ahmadi, Farhad AU - Briner, Myriam AU - Sédille-Mostafaie, Nazanin AU - Kilidireas, Constantinos AU - Stefanis, Leonidas AU - Chan, Andrew AU - Hoepner, Robert AU - Evangelopoulos, Maria Eleftheria T2 - Therapeutic Advances in Neurological Disorders AB - Background: In multiple sclerosis (MS), the frequency of hypogammaglobulinemia is unknown. We aimed to evaluate the frequency of reduced immunoglobulin (Ig) concentrations and its association with immunotherapy and disease course in two independent MS cohorts. Methods: In our retrospective cross-sectional study, MS patients and control patients with head or neck pain from Bern University Hospital (Bern, Switzerland) and Eginition University Hospital (Athens, Greece) were included. The lower limits of normal (LLN) for serum Ig concentration were IgG < 700 mg/dl, IgM < 40 mg/dl, and IgA < 70 mg/dl. Mann–Whitney U test, analysis of variance test, and multiple linear regression analysis were employed. Results: In total, 327 MS patients were retrospectively identified (Bern/Athens: n = 226/101). Serum IgG concentrations were frequently under LLN in both MS cohorts (Bern/Athens: 15.5%/14.9%), even when considering only untreated patients (Bern/Athens: 7.9%/8.6%). MS patients ( n = 327) were significantly more likely to have IgG concentrations below LLN and below 600 mg/dl in comparison with controls ( n = 58) ( p = 0.015 and 0.047, respectively). Between both patient groups, no significant differences were found in frequencies of IgA and IgM concentrations under LLN [ n (MS patients/controls): IgA 203/30, IgM 224/24]. Independently of age, secondary progressive MS patients had lower IgG concentrations than relapsing–remitting and primary progressive patients (both: p ⩽ 0.01). After adjusting for sex, age, and disease course, IgG concentrations were lower in patients treated with rituximab ( p = 0.001; n = 42/327), intravenous corticosteroids ( p < 0.001; n = 16/327), natalizumab ( p < 0.001; n = 48/327), and fingolimod ( p = 0.003; n = 6/327). Conclusion: Our study demonstrated high prevalence rates of reduced serum IgG concentrations in MS patients with and without disease-modifying treatments. The significance of lower IgG concentrations at the levels noted is unclear considering that infections or interference with antibody production generally occur when IgG levels are much lower, at or below 400 mg/dl. However, the information is useful to monitor IgG levels especially with anti-B-cell therapies and consider IgG substitution when levels drop below 400 mg/dl. DA - 2019/01// PY - 2019 DO - 10.1177/1756286419878340 DP - DOI.org (Crossref) VL - 12 SP - 175628641987834 J2 - Ther Adv Neurol Disord LA - en SN - 1756-2864, 1756-2864 ST - Reduced serum immunoglobulin G concentrations in multiple sclerosis UR - http://journals.sagepub.com/doi/10.1177/1756286419878340 Y2 - 2021/02/24/22:30:11 KW - peer-reviewed ER - TY - JOUR TI - Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species AU - Nachman, Eliana AU - Wentink, Anne S. AU - Madiona, Karine AU - Bousset, Luc AU - Katsinelos, Taxiarchis AU - Allinson, Kieren AU - Kampinga, Harm AU - McEwan, William A. AU - Jahn, Thomas R. AU - Melki, Ronald AU - Mogk, Axel AU - Bukau, Bernd AU - Nussbaum-Krammer, Carmen T2 - Journal of Biological Chemistry DA - 2020/07// PY - 2020 DO - 10.1074/jbc.RA120.013478 DP - DOI.org (Crossref) VL - 295 IS - 28 SP - 9676 EP - 9690 J2 - Journal of Biological Chemistry LA - en SN - 00219258 UR - https://linkinghub.elsevier.com/retrieve/pii/S0021925817489836 Y2 - 2021/02/24/21:44:47 KW - peer-reviewed ER - TY - JOUR TI - Interaction of the chaperones alpha B-crystallin and CHIP with fibrillar alpha-synuclein: Effects on internalization by cells and identification of interacting interfaces AU - Bendifallah, Maya AU - Redeker, Virginie AU - Monsellier, Elodie AU - Bousset, Luc AU - Bellande, Tracy AU - Melki, Ronald T2 - Biochemical and Biophysical Research Communications DA - 2020/06// PY - 2020 DO - 10.1016/j.bbrc.2020.04.091 DP - DOI.org (Crossref) VL - 527 IS - 3 SP - 760 EP - 769 J2 - Biochemical and Biophysical Research Communications LA - en SN - 0006291X ST - Interaction of the chaperones alpha B-crystallin and CHIP with fibrillar alpha-synuclein UR - https://linkinghub.elsevier.com/retrieve/pii/S0006291X20308172 Y2 - 2021/02/24/21:39:37 KW - peer-reviewed ER - TY - JOUR TI - TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration AU - Russ, Kaspar AU - Teku, Gabriel AU - Bousset, Luc AU - Redeker, Virginie AU - Piel, Sara AU - Savchenko, Ekaterina AU - Pomeshchik, Yuriy AU - Savistchenko, Jimmy AU - Stummann, Tina C. AU - Azevedo, Carla AU - Collin, Anna AU - Goldwurm, Stefano AU - Fog, Karina AU - Elmer, Eskil AU - Vihinen, Mauno AU - Melki, Ronald AU - Roybon, Laurent T2 - Cell Reports DA - 2021/03// PY - 2021 DO - 10.1016/j.celrep.2021.108895 DP - DOI.org (Crossref) VL - 34 IS - 12 SP - 108895 J2 - Cell Reports LA - en SN - 22111247 UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124721002096 Y2 - 2021/03/26/20:24:38 KW - peer-reviewed ER - TY - JOUR TI - Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold AU - Falcon, Benjamin AU - Zhang, Wenjuan AU - Schweighauser, Manuel AU - Murzin, Alexey G. AU - Vidal, Ruben AU - Garringer, Holly J. AU - Ghetti, Bernardino AU - Scheres, Sjors H. W. AU - Goedert, Michel T2 - Acta Neuropathologica DA - 2018/11// PY - 2018 DO - 10.1007/s00401-018-1914-z DP - DOI.org (Crossref) VL - 136 IS - 5 SP - 699 EP - 708 J2 - Acta Neuropathol LA - en SN - 0001-6322, 1432-0533 UR - http://link.springer.com/10.1007/s00401-018-1914-z Y2 - 2021/03/26/20:23:19 KW - peer-reviewed ER - TY - JOUR TI - Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading AU - Kundel, Franziska AU - Hong, Liu AU - Falcon, Benjamin AU - McEwan, William A. AU - Michaels, Thomas C. T. AU - Meisl, Georg AU - Esteras, Noemi AU - Abramov, Andrey Y. AU - Knowles, Tuomas J. P. AU - Goedert, Michel AU - Klenerman, David T2 - ACS Chemical Neuroscience DA - 2018/06/20/ PY - 2018 DO - 10.1021/acschemneuro.8b00094 DP - DOI.org (Crossref) VL - 9 IS - 6 SP - 1276 EP - 1282 J2 - ACS Chem. Neurosci. LA - en SN - 1948-7193, 1948-7193 UR - https://pubs.acs.org/doi/10.1021/acschemneuro.8b00094 Y2 - 2021/03/26/20:21:52 KW - peer-reviewed ER - TY - JOUR TI - LRRK2 modifies α-syn pathology and spread in mouse models and human neurons AU - Bieri, Gregor AU - Brahic, Michel AU - Bousset, Luc AU - Couthouis, Julien AU - Kramer, Nicholas J. AU - Ma, Rosanna AU - Nakayama, Lisa AU - Monbureau, Marie AU - Defensor, Erwin AU - Schüle, Birgitt AU - Shamloo, Mehrdad AU - Melki, Ronald AU - Gitler, Aaron D. T2 - Acta Neuropathologica DA - 2019/06// PY - 2019 DO - 10.1007/s00401-019-01995-0 DP - DOI.org (Crossref) VL - 137 IS - 6 SP - 961 EP - 980 J2 - Acta Neuropathol LA - en SN - 0001-6322, 1432-0533 UR - http://link.springer.com/10.1007/s00401-019-01995-0 Y2 - 2021/03/26/20:18:25 KW - peer-reviewed ER - TY - JOUR TI - How is alpha‐synuclein cleared from the cell? AU - Stefanis, Leonidas AU - Emmanouilidou, Evangelia AU - Pantazopoulou, Marina AU - Kirik, Deniz AU - Vekrellis, Kostas AU - Tofaris, George K. T2 - Journal of Neurochemistry DA - 2019/09// PY - 2019 DO - 10.1111/jnc.14704 DP - DOI.org (Crossref) VL - 150 IS - 5 SP - 577 EP - 590 J2 - J. Neurochem. LA - en SN - 0022-3042, 1471-4159 UR - https://onlinelibrary.wiley.com/doi/abs/10.1111/jnc.14704 Y2 - 2020/11/20/17:55:53 KW - peer-reviewed ER - TY - JOUR TI - The Role of Antibodies and Their Receptors in Protection Against Ordered Protein Assembly in Neurodegeneration AU - Katsinelos, Taxiarchis AU - Tuck, Benjamin J. AU - Mukadam, Aamir S. AU - McEwan, William A. T2 - Frontiers in Immunology DA - 2019/05/31/ PY - 2019 DO - 10.3389/fimmu.2019.01139 DP - DOI.org (Crossref) VL - 10 SP - 1139 J2 - Front. Immunol. SN - 1664-3224 UR - https://www.frontiersin.org/article/10.3389/fimmu.2019.01139/full Y2 - 2020/11/20/18:01:14 KW - peer-reviewed ER - TY - JOUR TI - The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding AU - Courte, Josquin AU - Bousset, Luc AU - Boxberg, Ysander Von AU - Villard, Catherine AU - Melki, Ronald AU - Peyrin, Jean-Michel T2 - Scientific Reports DA - 2020/12// PY - 2020 DO - 10.1038/s41598-020-61757-x DP - DOI.org (Crossref) VL - 10 IS - 1 SP - 4895 J2 - Sci Rep LA - en SN - 2045-2322 UR - http://www.nature.com/articles/s41598-020-61757-x Y2 - 2020/11/20/18:00:43 KW - peer-reviewed ER - TY - JOUR TI - Pharmacological Transdifferentiation of Human Nasal Olfactory Stem Cells into Dopaminergic Neurons AU - Chabrat, Audrey AU - Lacassagne, Emmanuelle AU - Billiras, Rodolphe AU - Landron, Sophie AU - Pontisso-Mahout, Amélie AU - Darville, Hélène AU - Dupront, Alain AU - Coge, Francis AU - Schenker, Esther AU - Piwnica, David AU - Nivet, Emmanuel AU - Féron, François AU - Mannoury la Cour, Clotilde T2 - Stem Cells International AB - The discovery of novel drugs for neurodegenerative diseases has been a real challenge over the last decades. The development of patient- and/or disease-specific in vitro models represents a powerful strategy for the development and validation of lead candidates in preclinical settings. The implementation of a reliable platform modeling dopaminergic neurons will be an asset in the study of dopamine-associated pathologies such as Parkinson’s disease. Disease models based on cell reprogramming strategies, using either human-induced pluripotent stem cells or transcription factor-mediated transdifferentiation, are among the most investigated strategies. However, multipotent adult stem cells remain of high interest to devise direct conversion protocols and establish in vitro models that could bypass certain limitations associated with reprogramming strategies. Here, we report the development of a six-step chemically defined protocol that drives the transdifferentiation of human nasal olfactory stem cells into dopaminergic neurons. Morphological changes were progressively accompanied by modifications matching transcript and protein dopaminergic signatures such as LIM homeobox transcription factor 1 alpha (LMX1A), LMX1B, and tyrosine hydroxylase (TH) expression, within 42 days of differentiation. Phenotypic changes were confirmed by the production of dopamine from differentiated neurons. This new strategy paves the way to develop more disease-relevant models by establishing reprogramming-free patient-specific dopaminergic cell models for drug screening and/or target validation for neurodegenerative diseases. DA - 2019/05/19/ PY - 2019 DO - 10.1155/2019/2945435 DP - DOI.org (Crossref) VL - 2019 SP - 1 EP - 15 J2 - Stem Cells International LA - en SN - 1687-966X, 1687-9678 UR - https://www.hindawi.com/journals/sci/2019/2945435/ Y2 - 2020/11/20/17:57:02 KW - peer-reviewed ER - TY - JOUR TI - α‐synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities AU - Alam, Parvez AU - Bousset, Luc AU - Melki, Ronald AU - Otzen, Daniel E. T2 - Journal of Neurochemistry DA - 2019/09// PY - 2019 DO - 10.1111/jnc.14808 DP - DOI.org (Crossref) VL - 150 IS - 5 SP - 522 EP - 534 J2 - J. Neurochem. LA - en SN - 0022-3042, 1471-4159 ST - α‐synuclein oligomers and fibrils UR - https://onlinelibrary.wiley.com/doi/abs/10.1111/jnc.14808 Y2 - 2020/11/20/18:01:49 KW - peer-reviewed ER - TY - JOUR TI - Spreading of α-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved AU - Vasili, Eftychia AU - Dominguez-Meijide, Antonio AU - Outeiro, Tiago Fleming T2 - Frontiers in Molecular Neuroscience DA - 2019/04/25/ PY - 2019 DO - 10.3389/fnmol.2019.00107 DP - DOI.org (Crossref) VL - 12 SP - 107 J2 - Front. Mol. Neurosci. SN - 1662-5099 ST - Spreading of α-Synuclein and Tau UR - https://www.frontiersin.org/article/10.3389/fnmol.2019.00107/full Y2 - 2020/11/20/17:57:40 KW - peer-reviewed ER - TY - JOUR TI - α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb AU - Rey, Nolwen L. AU - Bousset, Luc AU - George, Sonia AU - Madaj, Zachary AU - Meyerdirk, Lindsay AU - Schulz, Emily AU - Steiner, Jennifer A. AU - Melki, Ronald AU - Brundin, Patrik T2 - Acta Neuropathologica Communications AB - Alpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains. DA - 2019/12/30/ PY - 2019 DO - 10.1186/s40478-019-0859-3 DP - BioMed Central VL - 7 IS - 1 SP - 221 J2 - Acta Neuropathologica Communications SN - 2051-5960 UR - https://doi.org/10.1186/s40478-019-0859-3 Y2 - 2020/01/14/13:28:24 KW - peer-reviewed ER - TY - JOUR TI - Propagation of α-Synuclein Strains within Human Reconstructed Neuronal Network AU - Gribaudo, Simona AU - Tixador, Philippe AU - Bousset, Luc AU - Fenyi, Alexis AU - Lino, Patricia AU - Melki, Ronald AU - Peyrin, Jean-Michel AU - Perrier, Anselme L. T2 - Stem Cell Reports DA - 2019/01/10/ PY - 2019 DO - 10.1016/j.stemcr.2018.12.007 DP - www.cell.com VL - 0 IS - 0 J2 - Stem Cell Reports LA - English SN - 2213-6711 UR - https://www.cell.com/stem-cell-reports/abstract/S2213-6711(18)30526-5 Y2 - 2019/01/11/13:44:40 KW - Lewy body KW - Parkinson's disease KW - human cortical neuron KW - human pluripotent stem cells KW - microfluidic KW - neuronal dysfunction KW - nucleation KW - peer-reviewed KW - prion-like KW - synuclein ER - TY - JOUR TI - Tau Filaments and the Development of Positron Emission Tomography Tracers AU - Goedert, Michel AU - Yamaguchi, Yoshiki AU - Mishra, Sushil K. AU - Higuchi, Makoto AU - Sahara, Naruhiko T2 - Frontiers in Neurology DA - 2018/02/15/ PY - 2018 DO - 10.3389/fneur.2018.00070 DP - Crossref VL - 9 SN - 1664-2295 UR - http://journal.frontiersin.org/article/10.3389/fneur.2018.00070/full Y2 - 2018/11/26/15:56:27 KW - peer-reviewed ER - TY - JOUR TI - Neurodegeneration and the ordered assembly of α-synuclein AU - Spillantini, Maria Grazia AU - Goedert, Michel T2 - Cell and Tissue Research DA - 2018/07// PY - 2018 DO - 10.1007/s00441-017-2706-9 DP - Crossref VL - 373 IS - 1 SP - 137 EP - 148 LA - en SN - 0302-766X, 1432-0878 UR - http://link.springer.com/10.1007/s00441-017-2706-9 Y2 - 2018/11/26/16:20:59 KW - peer-reviewed ER - TY - JOUR TI - Allogeneic BK Virus-Specific T-Cell Treatment in 2 Patients With Progressive Multifocal Leukoencephalopathy AU - Hopfner, Franziska AU - Möhn, Nora AU - Eiz-Vesper, Britta AU - Maecker-Kolhoff, Britta AU - Gottlieb, Jens AU - Blasczyk, Rainer AU - Mahmoudi, Nima AU - Pars, Kaweh AU - Adams, Ortwin AU - Stangel, Martin AU - Wattjes, Mike P. AU - Höglinger, Günter AU - Skripuletz, Thomas T2 - Neurology - Neuroimmunology Neuroinflammation AB - Objective Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating opportunistic infection of the brain caused by the ubiquitously distributed JC polyomavirus. There are no established treatment options to stop or slow down disease progression. In 2018, a case series of 3 patients suggested the efficacy of allogeneic BK virus-specific T-cell (BKV-CTL) transplantation. Methods Two patients, a bilaterally lung transplanted patient on continuous immunosuppressive medication since 17 years and a patient with dermatomyositis treated with glucocorticosteroids, developed definite PML according to AAN diagnostic criteria. We transplanted both patients with allogeneic BKV-CTL from partially human leukocyte antigen (HLA) compatible donors. Donor T cells had directly been produced from leukapheresis by the CliniMACS IFN-γ cytokine capture system. In contrast to the previous series, we identified suitable donors by HLA typing in a preexamined registry and administered 1 log level less cells. Results Both patients' symptoms improved significantly within weeks. During the follow-up, a decrease in viral load in the CSF and a regression of the brain MRI changes occurred. The transfer seemed to induce endogenous BK and JC virus-specific T cells in the host. Conclusions We demonstrate that this optimized allogeneic BKV-CTL treatment paradigm represents a promising, innovative therapeutic option for PML and should be investigated in larger, controlled clinical trials. Classification of Evidence This study provides Class IV evidence that for patients with PML, allogeneic transplant of BKV-CTL improved symptoms, reduced MRI changes, and decreased viral load. DA - 2021/07// PY - 2021 DO - 10.1212/NXI.0000000000001020 DP - DOI.org (Crossref) VL - 8 IS - 4 SP - e1020 J2 - Neurol Neuroimmunol Neuroinflamm LA - en SN - 2332-7812 UR - http://nn.neurology.org/lookup/doi/10.1212/NXI.0000000000001020 Y2 - 2022/02/14/18:00:03 KW - peer-reviewed ER - TY - JOUR TI - A Critical Assessment of Exosomes in the Pathogenesis and Stratification of Parkinson’s Disease AU - Tofaris, George K. T2 - Journal of Parkinson's Disease DA - 2017/11/01/ PY - 2017 DO - 10.3233/JPD-171176 DP - Crossref VL - 7 IS - 4 SP - 569 EP - 576 SN - 18777171, 1877718X UR - http://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JPD-171176 Y2 - 2018/11/26/16:21:48 KW - peer-reviewed ER -