Imbalanced mitochondrial dynamics in human PD and α-synuclein mouse brains

Abstract

Emerging studies have shown that dysregulation in mitochondrial dynamics has a major negative impact on mitochondria. Partial genetic and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (DRP1) has been demonstrated to be beneficial in models of neurodegenerative disorders, including Parkinson's disease (PD). However, the expression of DRP1 and other mitochondrial fission/fusion mediators have not been investigated in the brains of Parkinson's patients. This information is critical to strengthening mitochondrial dynamics as a potential therapeutic target for PD. We report in this study that significant increases in the levels of both DNM1L, which encodes DRP1, as well as the DRP1 protein were detected in Parkinson's patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered. To complement these human studies and given the significant role of α-synuclein in PD pathogenesis, we performed time-course studies using transgenic mice overexpressing human wild-type SNCA. As early as six months old, we detected an upregulation of DRP1 in the nigral DA neurons of the SNCA mice as compared to their wild-type littermates. Furthermore, these mutant animals exhibited more DRP1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.

Keywords: Dynamin-related protein 1; Mitochondrial dynamics; Neurodegeneration; Parkinson's disease; Protein aggregation; α-synuclein.