Treatment Development for Parkinson's Disease
Parkinson’s disease (PD) is a neurodegenerative disorder with a slow and variable progression. Typically, symptoms appear after alpha-synuclein (alpha-syn) fibrils have accumulated in the cell, and this accumulation is a major constituent of Lewy bodies. The alpha-syn protein is encoded by the SNCA gene, and dominant mutations in this gene have been identified in rare familial versions of PD. These genetic and pathological findings support the hypothesis that progressive accumulation of aggregated alpha-syn is a central pathogenic process in PD.
Therefore, the development of a small molecule that disrupts the accumulation of alpha-syn fibrils could be valuable as a therapeutic approach. The process of fibril formation consists of two fundamental steps: 1) nucleation of oligomeric seeds by the association of two or more monomers, and 2) fibril growth mediated by sequential association of monomer with existing seeds. We have developed an in vitro fibril growth assay that uses fluorescence to measure the association of monomeric alpha-syn molecules with “seeds”. These "seeds" consist of preformed fibrils that are prepared from recombinant alpha-syn protein. We are currently using this assay to identify drug-like molecules that inhibit fibril growth.
- Dhavale DD, Tsai C, Bagchi DP, Engel LA, Sarezky J, Kotzbauer PT. (2017). A sensitive assay reveals structural requirements for α-synuclein fibril growth. J Biol Chem. 292(22):9034-9050. PubMed PMID: 28373279.