科研之友
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摘要
Alpha-synuclein (alpha-syn) is involved in both familial and sporadic Parkinson's disease (PD). One of the proposed pathogenic mechanisms of alpha-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by alpha-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against alpha-syn overexpression in vivo. To accomplish this goal, we overexpressed human A53T-alpha-synuclein (hA53T-alpha-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1). We show here that mdivi-1 reduced neurodegeneration, alpha-syn aggregates and normalized motor function. Mechanistically, mdivi-1 reduced mitochondrial fragmentation, mitochondrial dysfunction and oxidative stress. These in vivo results support the negative role of mutant alpha-syn in mitochondrial function and indicate that mdivi-1 has a high therapeutic potential for PD.
- 出版日期2017-8-8
