Defining α-synuclein species responsible for Parkinson’s disease phenotypes in mice

• Published in: The Journal of biological chemistry Vol. 294; no. 27; pp. 10392 - 10406
• Main Authors: Froula, Jessica M., Castellana-Cruz, Marta, Anabtawi, Nadia M., Camino, José D., Chen, Serene W., Thrasher, Drake R., Freire, Jennifer, Yazdi, Allen A., Fleming, Sheila, Dobson, Christopher M., Kumita, Janet R., Cremades, Nunilo, Volpicelli-Daley, Laura A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-07-2019; American Society for Biochemistry and Molecular Biology
• Subjects: alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; alpha-Synuclein - pharmacology; amyloid; Amyloid - metabolism; Animals; Behavior, Animal - drug effects; Corpus Striatum - metabolism; cytotoxicity; Disease Models, Animal; Dopaminergic Neurons - metabolism; Editors' Picks; fibril; Lewy body; Male; Mice; motor-behavior defect; neurodegenerative disease; oligomer; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Phenotype; Protein Aggregates; protein aggregation; Protein Conformation, beta-Strand; α-synuclein; fibril; Parkinson's disease; amyloid; neurodegenerative disease; protein aggregation; oligomer; motor-behavior defect; α-synuclein; cytotoxicity; Lewy body
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.007743

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregated α-synuclein (α-syn). These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions to halt disease progression. α-Synuclein exists in multiple structural forms, including disordered, nonamyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable β-amyloid–sheet oligomers compared with those of fibrillar α-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different α-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found that β-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small β-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor-behavior defects. We conclude that although the β-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric α-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation of β-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders.