Structurally distinct ?-synuclein fibrils induce robust parkinsonian pathology.

ABSTRACT: OBJECTIVE:Alpha-synuclein (?-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with ?-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for ?-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of ?-syn G51D mutation using a murine model generated by G51D ?-syn fibril injection into the brain. METHODS:Structural analysis of wild-type and G51D ?-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of ?-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of ?-syn fibrils was then used to evaluate the propagation pattern of ?-syn and related cellular changes. RESULTS:We found that G51D ?-syn fibrils have higher ?-sheet contents than wild-type ?-syn fibrils. The addition of G51D ?-syn fibrils to mammalian cells overexpressing ?-syn resulted in the formation of phosphorylated ?-syn inclusions at a higher rate. Similarly, an injection of G51D ?-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated ?-syn pathology. Notably, the mice injected with G51D ?-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment. CONCLUSION:Our findings indicate that the structural difference of G51D ?-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

SUBMITTER: Hayakawa H 

PROVIDER: S-EPMC7202333 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature