IMPRiND Project

RESEARCH HIGHLIGHT – A stem cell-based model offers new insights into the mechanisms of neuronal loss in Parkinson’s disease

Dr Tofaris and his team at UOXF in collaboration with Ronald Melki (CNRS) have now come up with a working laboratory model. They used induced pluripotent stem cells (iPSC) derived from both healthy subjects and patients with the alpha-synuclein gene defects to generate human dopaminergic neurons that are primarily affected in Parkinson’s disease. They found a way of ‘amplifying’ in a fairly pure form, the main constituent, called fibril, of alpha-synuclein clumps directly from post-mortem Parkinson’s brains. When they added these brain-derived fibrils onto the human dopaminergic neurons, they successfully triggered the aggregation of alpha-synuclein inside the cells and observed progressive neuronal loss.

Reporting in Nature Communications, Tanudjojo et al. used this model to show that the two main determinants of neuronal death are: (a) the abundance of alpha-synuclein inside nerve cells, and (b) the structure it acquires when it assembles into aggregates. By tracking the molecular interactions of the toxic forms of alpha-synuclein aggregates in living cells, they discovered that they cause damage partly by evading the protective effects of PARK7/DJ-1. Deletion of DJ-1 in iPSC-derived neurons increased alpha-synuclein aggregation and neuronal death. This could explain why loss of function mutations in DJ-1 in patients causes Parkinson’s disease.

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RESEARCH HIGHLIGHT - Structures of alpha-synuclein filaments from multiple system atrophy

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RESEARCH HIGHLIGHT - Cryo-EM structures of tau filaments from Alzheimer's disease

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RESEARCH HIGHLIGHT - Journey to the centre of pathogenic alpha-synuclein aggregate

The protein alpha-synuclein aggregates are constituents of Lewy bodies, a histological hallmark of the synuceinopathies Parkinson's disease, Lewy body dementia and multiple system atrophy.

Elucidating the forms alpha-synuclein molecules adopt upon staking within aggregates is key for the design of ligands targeting those aggregates. Such ligands could attach along or at the ends of the resulting fibrils and affect their surface properties or their ability to elongate and thus limit the pathological processes involved in synucleinopathies.

Partner CNRS within a collaborative study with experts in Cryo-Electron microscopy recently determined a new structure for alpha-synuclein fibrils, down to an atomic level. Those fibrils, when injected into rodent models, cause the development of symptoms characteristic of Parkinson's disease.

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This project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking ( under grant agreement No 116060. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038.

The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.

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