Familial Parkinson's point mutation abolishes multiple system atrophy prion replication

In the neurodegenerative disease multiple system atrophy (MSA), alpha-synudein misfolds into a self-templating conformation to become a prion. To compare the biological activity of alpha-synudein prions in MSA and Parkinson's disease (PD), we developed nine alpha-synudein-YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T alpha-synudein-YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA alpha-synudein prions are conformationally distinct from the misfolded alpha-synudein in PD patients. This observation may have profound implications for developing treatments for neurodegenerative diseases.