7,8-Dihydroxyflavone ameliorates mitochondrial impairment and motor dysfunction in the α-synuclein 1–103 transgenic mice

Parkinson's disease (PD) is the most common motor-associated neurodegenerative disease. Although the pathogenesis of PD is still wrapped in the mist, accumulating evidence indicates that mitochondrial dysfunction contributes to the onset and progression of PD. We previously reported that the lysosomal protease asparagine endopeptidase (AEP) cleaves α-synuclein in the brains of PD patients. The major product, α-synuclein 1–103, significantly promotes PD-like histological changes and motor dysfunction. However, the underlying molecular mechanisms remain unknown. Here we show that α-synuclein 1–103 fragment interacts with mitochondria and induces morphological and functional abnormalities of mitochondria. Furthermore, we investigated the protective effects of 7,8-dihydroxyflavone (7,8-DHF) on mitochondrial dysfunction induced by α-synuclein 1–103 fragment. We found that 7,8-DHF ameliorated α-synuclein 1–103-induced mitochondrial impairment and motor dysfunction. These results indicate that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating PD. [Display omitted] •α-Synuclein 1–103 induces mitochondrial impairments in cellular and N103 mouse models.•7,8-DHF ameliorates α-synuclein 1–103-induced mitochondrial dysfunctions.•PD-like pathology and motor symptoms of N103 mice could be alleviated by 7,8-DHF.