Abstract
Aberrant secretion and accumulation of α-synuclein (α-Syn) as well as the loss of parkin function are associated with the pathogenesis of Parkinson’s disease (PD). Our previous study suggested a functional interaction between those two proteins, showing that the extracellular α-Syn evoked post-translational modifications of parkin, leading to its autoubiquitination and degradation. While parkin plays an important role in mitochondrial biogenesis and turnover, including mitochondrial fission/fusion as well as mitophagy, the involvement of parkin deregulation in α-Syn-induced mitochondrial damage is largely unknown. In the present study, we demonstrated that treatment with exogenous α-Syn triggers mitochondrial dysfunction, reflected by the depolarization of the mitochondrial membrane, elevated synthesis of the mitochondrial superoxide anion, and a decrease in cellular ATP level. At the same time, we observed a protective effect of parkin overexpression on α-Syn-induced mitochondrial dysfunction. α-Syn-dependent disturbances of mitophagy were also shown to be directly related to reduced parkin levels in mitochondria and decreased ubiquitination of mitochondrial proteins. Also, α-Syn impaired mitochondrial biosynthesis due to the parkin-dependent reduction of PGC-1α protein levels. Finally, loss of parkin function as a result of α-Syn treatment induced an overall breakdown of mitochondrial homeostasis that led to the accumulation of abnormal mitochondria. These findings may thus provide the first compelling evidence for the direct association of α-Syn-mediated parkin depletion to impaired mitochondrial function in PD. We suggest that improvement of parkin function may serve as a novel therapeutic strategy to prevent mitochondrial impairment and neurodegeneration in PD (thereby slowing the progression of the disease).
Highlights
Parkinson’s disease (PD) is a widespread progressive movement disorder and one of the most common neurodegenerative diseases, characterized by a degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) projecting into the basal ganglia
A plethora of studies have demonstrated that deposition of α-Syn in Lewy bodies, parkin impairment, and mitochondria dysfunction are key features of PD pathology (Jesko et al, 2019)
This study is the first to show that exogenous α-Syn leads to disturbances in parkin-dependent mechanisms of mitophagy, resulting in the accumulation of defective mitochondria and that the overexpression of parkin ameliorates the mitochondrial dysfunction evoked by α-Syn oligomers
Summary
Parkinson’s disease (PD) is a widespread progressive movement disorder and one of the most common neurodegenerative diseases, characterized by a degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) projecting into the basal ganglia. Only a few studies have investigated the direct association between α-Syn and parkin dysfunctions, mutations in both proteins have long been considered major causes of hereditary PD. While many studies have highlighted the direct association of the pathological pool of α-Syn with mitochondrial dysfunction (Banerjee et al, 2010; Wilkaniec et al, 2013; Ganjam et al, 2019), it is largely unknown whether impairment in parkin-dependent mitophagy might have an important role in PD, especially since it has been demonstrated that parkin knockout mice did not display a neurodegenerative phenotype (Pickrell and Youle, 2015). In a mouse model with accelerated mtDNA mutations resulting in the accumulation of dysfunctional mitochondria, the absence of parkin caused a dramatic loss of DA neurons in the SNpc (Pickrell et al, 2015). This study was designed to study whether exogenous α-Syn might be the trigger that leads to parkin-related mitochondrial damage
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