Abstract
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.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder characterized by bradykinsesia, muscular rigidity, rest tremor, and postural and gait impairment
We identify p38 mitogen-activated protein kinase (MAPK) acts as the upstream of Parkin and negatively regulates Parkin’s activity via phosphorylation, revealing that p38 MAPK activation leads to cell death and synapse loss through disrupting mitophagy
Hwang et al have reported that p38 MAPK activation inhibits autophagy and causes mitochondrial impairment by an unknown mechanism in PD3
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder characterized by bradykinsesia, muscular rigidity, rest tremor, and postural and gait impairment. Published evidence supports that α-synuclein aggregation and mitochondrial dysfunction are the main causes contributes to the progressive neuronal degeneration of PD1. Mutations in α-synuclein, including A53T mutant, result in autosomal dominant form of familial PD. An ubiquitin E3 ligase, plays a neuroprotective role in clearing dysfunctional mitochondria through mitophagy, protects neurons from α-synuclein toxicity and kinase-induced excitotoxicity[3]. Loss-of-function of Parkin results in mitochondrial dysfunction, which is a core pathogenic process in PD. A variety of posttranslational modifications of Parkin have been proved that affect its ubiquitin E3 ligase activation, including phosphorylation, ubiquitylation, and S-nitrosylation.[4,5]. Parkin’s function may be regulated by multiple factors
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