p38 MAPK-DRP1 signaling is involved in mitochondrial dysfunction and cell death in mutant A53T α-synuclein model of Parkinson's disease

Abnormal accumulation of alpha-synuclein and mitochondria dynamics dysfunction are considered to be implicated in the pathogenesis of Parkinson's disease. However, the underlying mechanisms how alpha-synuclein abnormal accumulation causes mitochondrial dynamics dysfunction remains unclear. Here, we demonstrate that dynamin-related protein 1(DRP1) is a substrate for p38 MAPK, mutant alpha-synuclein overexpression in SN4741 cell caused p38 MAPK activation, p38 MAPK-mediated phosphorylation DRP1 at serine 616 to activate DRP1 and is associated with increased mitochondrial fission, which resulted in mitochondrial dysfunction and neuronal loss. Inhibition of p38 MAPK or expression of a kinase death form of p38 MAPK not only attenuates DRP1-mediated mitochondrial fission, but also restores the mitochondrial dysfunction and cell death in alpha-synuclein A53T model. These findings showed that inhibition of p38 MAPK-DRP1 signaling pathway may be a viable therapeutic strategy of PD on maintenance of mitochondrial homeostasis.