CHAPERONES IN ND · The Role of Molecular Chaperones in Parkinson' s Disease

Parkinson's disease is a severe human neurodegenerative disorder that affects mainly the aging generation. It is characterized by the loss of dopaminergic neurons from the substantia nigra, and the formation Lewy bodies, intraneuronal inclusions which are primarily composed of fibrillar alpha-synuclein. Several lines of evidence support a role for molecular chaperones as modulators of alpha-synuclein aggregation and toxicity in Parkinson's disease. Current findings suggest that prevention and/or the reversion of alpha-synuclein aggregation by molecular chaperones may constitute a promising therapeutic approach for the treatment of Parkinson’s disease and related disorders. However, the molecular and structural bases underlying the mechanisms by which molecular chaperones modulate protein aggregation and amyloid formation are yet poorly understood. The overall objective of this proposal is to gain a detailed mechanistic insight into the structural and molecular mechanisms by which molecular chaperones modulate protein aggregation and neurotoxicity in vitro using cellular models of synucleinopathies. We will focus on the functional relationship of the molecular chaperones Hsp70, Hsp40, Hsp90, and, Hsp27 that have been linked to Parkinson’s disease. In addition, we will assay the impact of Hsp104, which is the protein disaggregation machinery from yeast, on alpha-synuclein aggregation and toxicity. Thereby, we will seek to elucidate the molecular mechanisms by which molecular chaperones interact with alpha-synuclein and modulate its structural and aggregation properties in vitro, and we will probe the ability of molecular chaperones to prevent and/or rescue alpha-synuclein cytotoxicity in cellular models of synucleinopathies, including primary neuronal cell cultures. Such a detailed understanding of the molecular mechanisms by which cytosolic chaperones modulate alpha-synuclein aggregation and toxicity could provide viable targets for therapeutic strategies.