Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation.

Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
The Journal of clinical investigation (Impact Factor: 15.39). 03/2009; 119(3):650-60. DOI: 10.1172/JCI37617
Source: PubMed

ABSTRACT Mutations in PARKIN, pten-induced putative kinase 1 (PINK1), and DJ-1 are individually linked to autosomal recessive early-onset familial forms of Parkinson disease (PD). Although mutations in these genes lead to the same disease state, the functional relationships between them and how their respective disease-associated mutations cause PD are largely unknown. Here, we show that Parkin, PINK1, and DJ-1 formed a complex (termed PPD complex) to promote ubiquitination and degradation of Parkin substrates, including Parkin itself and Synphilin-1 in neuroblastoma cells and human brain lysates. Genetic ablation of either Pink1 or Dj-1 resulted in reduced ubiquitination of endogenous Parkin as well as decreased degradation and increased accumulation of aberrantly expressed Parkin substrates. Expression of PINK1 enhanced Parkin-mediated degradation of heat shock-induced misfolded protein. In contrast, PD-pathogenic Parkin and PINK1 mutations showed reduced ability to promote degradation of Parkin substrates. This study identified a functional ubiquitin E3 ligase complex consisting of PD-associated Parkin, PINK1, and DJ-1 to promote degradation of un-/misfolded proteins and suggests that their PD-pathogenic mutations impair E3 ligase activity of the complex, which may constitute a mechanism underlying PD pathogenesis.

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    ABSTRACT: Mitochondrial dysfunction has been reported in both familial and sporadic Parkinson's disease (PD). However, effective therapy targeting this pathway is currently inadequate. Recent studies suggest that manipulating the processes of mitochondrial fission and fusion has considerable potential for treating human diseases. To determine the therapeutic impact of targeting these pathways on PD, we used two complementary mouse models of mitochondrial impairments as seen in PD. We show here that blocking mitochondrial fission is neuroprotective in the PTEN-induced putative kinase-1 deletion (PINK1(-/-)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models. Specifically, we show that inhibition of the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) using gene-based and small-molecule approaches attenuates neurotoxicity and restores pre-existing striatal dopamine release deficits in these animal models. These results suggest Drp1 inhibition as a potential treatment for PD.
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    ABSTRACT: Significance. Disruptions in mitochondrial homeostasis are implicated in human diseases across the lifespan. Recessive mutations in PINK1, which encodes the mitochondrially-targeted PTEN-induced putative kinase 1 (PINK1), cause an autosomal recessive form of Parkinson's disease. As with all kinases, PINK1 participates in multiple functional pathways, and its dysregulation has been implicated in a growing number of diseases. Recent Advances. In addition to its heavily studied role in mitophagy, PINK1 regulates mitochondrial respiratory function, reactive oxygen species generation and mitochondrial transport. Moreover, recent studies implicate processed PINK1 in cytosolic signaling cascades that promote cell survival and neuron differentiation. Cytosolic PINK1 is also capable of suppressing autophagy and mitophagy. We propose a working hypothesis that PINK1 is released by functional mitochondria as a signal to coordinate cell growth and differentiation in response to mitochondrial status. Critical Issues. PINK1 biology needs to be better understood in primary neurons, as the stability and subcellular localization of PINK1 is differentially regulated in different cell types. Delineating factors that regulate its mitochondrial import/export, processing by different peptidases, kinase activity, subcellular localization and degradation will be important for defining relevant downstream kinase targets. Future Directions. It is becoming clear that different subcellular pools of PINK1 mediate distinct functions. Future studies will undoubtedly expand upon the spectrum of cellular functions regulated by PINK1. Continued study of cytosolic PINK1 may offer novel insights into how functional mitochondria communicate their status with the rest of the cell.
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