New research has identified a shortened variant of α-synuclein that binds to mitochondria in neurons and induces their destruction. Investigators found that this conformationally distinct form of α-synuclein, termed pα-syn*, is present in cultured primary neurons treated with preformed fibrils of α-synuclein, in Parkinson disease (PD) model mice and in patients with PD. The study showed that the presence of pα-syn* results from failure by the cell to break down fibrillar aggregates of α-synuclein in the lysosome. After release from the lysosome, pα-syn* binds to mitochondria, inducing depolarization of the mitochondrial membrane, mitochondrial fragmentation and mitophagy. This neurotoxic species could represent a crucial player in PD pathogenesis and could be a target of future treatments for patients with the condition.
References
Grassi, D. et al. Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson's disease. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.1713849115 (2018)
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Ridler, C. Truncated α-synuclein causes mitochondrial toxicity. Nat Rev Neurol 14, 252 (2018). https://doi.org/10.1038/nrneurol.2018.33
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DOI: https://doi.org/10.1038/nrneurol.2018.33