@article{van_der_perren_structural_2020,
	title = {The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with Lewy bodies},
	volume = {139},
	issn = {1432-0533},
	url = {https://doi.org/10.1007/s00401-020-02157-3},
	doi = {10.1007/s00401-020-02157-3},
	abstract = {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 (α{SYN}) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar α{SYN} polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different α{SYN} strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct α{SYN} strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of α{SYN} assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of α{SYN} aggregates found in the brain of patients suffering from {PD}, {MSA} or {DLB} to seed and template monomeric human α{SYN} in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified α{SYN} fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of α{SYN} 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, α{SYN} 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.},
	pages = {977--1000},
	number = {6},
	journaltitle = {Acta Neuropathologica},
	shortjournal = {Acta Neuropathol},
	author = {Van der Perren, Anke and Gelders, Géraldine and Fenyi, Alexis and Bousset, Luc and Brito, Filipa and Peelaerts, Wouter and Van den Haute, Chris and Gentleman, Steve and Melki, Ronald and Baekelandt, Veerle},
	urldate = {2020-06-02},
	date = {2020-06-01},
	langid = {english},
	keywords = {highlight, peer-reviewed},
}