Single Molecule FRET Characterization of Oligomers from Alpha-Synuclein Early Onset Parkinson's Disease Mutants

Abstract

Parkinson's disease is the most diffused neurodegenerative disease involving movements. The protein alpha-synuclein must be linked to the disease by two lines of evidence: first, amyloid-like fibrils of the protein are found in patients' brains; second, three missense mutations in the gene of alpha-synuclein and the gene triplication itself cause autosomal dominant early onset forms of the disease. Recent outcomes underlined that alpha-synuclein oligomers are toxic for cells and may be responsible for cell death in Parkinson's disease. The precise role of oligomers in the etiopathogenesis of the disease is still under debate. In this study we use single molecule FRET to catch differences in the overall structure of oligomers generated from wild-type and A53T, A30P and E46K mutants. FRET efficiencies distributions reported by the mutants oligomers sets are different compared to the wild-type protein. This opens the possibility that oligomers with different structures may have different targets or may be differently processed by cells. Results obtained with this technique may contribute to the understanding of early onset Parkinson's disease generated by the mutants.