Pathologic and therapeutic implications for the cell biology of parkin

Abstract

Mutations in the E3 ligase parkin are the most common cause of autosomal recessive Parkinson's disease (PD), but it is believed that parkin dysfunction may also contribute to idiopathic PD. Since its discovery, parkin has been implicated in supporting multiple neuroprotective pathways, many revolving around the maintenance of mitochondrial health quality control and governance of cell survival. Recent advances across the structure, biochemistry, and cell biology of parkin have provided great insights into the etiology of parkin-linked and idiopathic PD and may ultimately generate novel therapeutic strategies to slow or halt disease progression. This review describes the various pathways in which parkin acts and the mechanisms by which parkin may be targeted for therapeutic intervention.

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

“…As a ubiquitously expressed E3 ligase, parkin has been shown to be involved in the UPS, and studies in parkin overexpression have confirmed enhanced proteasome activity (Khandelwal, 2010). Screening for parkin substrates has identified hundreds of proteins, including proteins involved in the epidermal growth factor pathway, Wnt signaling, inflammation, mitochondrial homeostasis, Lewy body formation, and apoptosis, suggesting broad involvement of parkin ubiquitination (Charan and LaVoie, 2015; von Coelln et al, 2004). Lack of parkin activity would suggest an accumulation of its substrates, leading to aberrant cell signaling and neurotoxicity.…”

“…Parkin’s neuroprotective role has been extensively observed in a variety of oxidative stress conditions, including mitochondrial, ER, proteolytic, and dopamine stress (Charan and LaVoie, 2015). Though parkin’s primary function in mediating oxidative stress appears to be in regulating mitophagy, it has been implicated in other pro-survival roles.…”

“…These prosurvival factors, including mitochondrial fusion regulator OPA1, prevent cytochrome c release, maintain mitochondrial integrity, and inhibit stress-induced cell death. Additionally, several studies suggest that parkin may interact with pro-apoptotic Bax and anti-apoptotic Bcl-2; however, the precise mechanism by which parkin interacts with Bcl-2 family proteins to regulate cell death remains unclear (Charan and LaVoie, 2015). …”

“…Many post-translational modifications, such as s-nitrosylation, oxidation, phosphorylation, and dopamine conjugation, reduce the stability and solubility of parkin, resulting in diminished activity (Charan and LaVoie, 2015). Melatonin, taurine, and vitamin have been shown to protect against oxidative stress and may protect parkin against some of these detrimental modifications.…”

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

“…66,67 These discordances may be explained by considering that interaction of the mitochondrial mutation pattern with mtQC-mitophagy is a complex process dependent on multiple factors, such as cell bioenergetics, culture conditions, level of PARK2 expression, cell-type and specific mtDNA mutations. 68 Of note, our data were obtained in cells containing the same mutation and were grown in identical culture conditions therefore minimizing the factors that strongly influence bioenergetic status, morphology and dynamics of mitochondria. 28,69 Therefore, the differences observed in mtQC and bioenergetics are due to the respective cell-type specificity.…”