P38 MAPK tarafından serine 131'de Parkin'in fosforilasyonu, Parkinson hastalığının mutant A53T ⁇ -sinüklein modelinde mitokondriyal disfonksiyon ve nöronal ölümü teşvik eder.

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α-synuclein abnormal accumulation and mitochondria dysfunction are involved in the pathogenesis of Parkinson's disease. Selective autophagy of mitochondria (mitophagy) is a crucial component of the network controlling the mitochondrial homeostasis. However, the underlying mechanism that mutant α-synuclein induces mitochondrial abnormality through mitophagy impairment is not fully understood. Here, we showed that mutant A53T α-synuclein accumulation impaired mitochondrial function and Parkin-mediated mitophgy in α-synucleinA53T model. α-synucleinA53T overexpression caused p38 MAPK activation, then p38 MAPK directly phosphorylated Parkin at serine 131 to disrupt the Parkin's protective function. The p38 MAPK inhibition significantly reduced cellular apoptosis, restored mitochondrial membrane potential as well as increased synaptic density both in SN4741 cells and primary midbrain neurons. These findings show that the p38 MAPK-Parkin signaling pathway regulates mitochondrial homeostasis and neuronal degeneration, which may be a potential therapeutic strategy of PD via enhancing mitochondrial turn-over and maintenance.

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