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

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

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

Journal of Biological Chemistry

2019

2019-07

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregatedβ-synuclein (β-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. β-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 α-amyloid-sheet oligomers compared with those of fibrillar β-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 β-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found thatα-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small α-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 theα-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric β-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 ofα-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders. [ABSTRACT FROM AUTHOR]

DOPAMINERGIC neurons; FOURIER transform infrared spectroscopy; MOUSE diseases; PARKINSON'S disease; SPECIES; SUBSTANTIA nigra

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