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Parkin is an E3 ubiquitin-ligase for normal and mutant ataxin-2 and prevents ataxin-2-induced cell death.

ABSTRACT: Expansion of the polyQ repeat in ataxin-2 results in degeneration of Purkinje neurons and other neuronal groups including the substantia nigra in patients with spinocerebellar ataxia type 2 (SCA2). In animal and cell models, overexpression of mutant ataxin-2 induces cell dysfunction and death, but little is known about steady-state levels of normal and mutant ataxin-2 and cellular mechanisms regulating their abundance. Based on preliminary findings that ataxin-2 interacted with parkin, an E3 ubiquitin ligase mutated in an autosomal recessive form of Parkinsonism, we sought to determine whether parkin played a role in regulating the steady-state levels of ataxin-2. Parkin interacted with the N-terminal half of normal and mutant ataxin-2, and ubiquitinated the full-length form of both wild-type and mutant ataxin-2. Parkin also regulated the steady-state levels of endogenous ataxin-2 in PC12 cells with regulatable parkin expression. Parkin reduced abnormalities in Golgi morphology induced by mutant ataxin-2 and decreased ataxin-2 induced cytotoxicity. In brains of SCA2 patients, parkin labeled cytoplasmic ataxin-2 aggregates in Purkinje neurons. These studies suggest a role for parkin in regulating the intracellular levels of both wild-type and mutant ataxin-2, and in rescuing cells from ataxin-2-induced cytotoxicity. The role of parkin variants in modifying the SCA2 phenotype and its use as a therapeutic target should be further investigated.

SUBMITTER: Huynh DP

PROVIDER: S-EPMC2788988 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Parkin is an E3 ubiquitin-ligase for normal and mutant ataxin-2 and prevents ataxin-2-induced cell death.

Huynh Duong P DP Nguyen Dung T DT Pulst-Korenberg Johannes B JB Brice Alexis A Pulst Stefan-M SM

Experimental neurology 20061109 2

Expansion of the polyQ repeat in ataxin-2 results in degeneration of Purkinje neurons and other neuronal groups including the substantia nigra in patients with spinocerebellar ataxia type 2 (SCA2). In animal and cell models, overexpression of mutant ataxin-2 induces cell dysfunction and death, but little is known about steady-state levels of normal and mutant ataxin-2 and cellular mechanisms regulating their abundance. Based on preliminary findings that ataxin-2 interacted with parkin, an E3 ubi ...[more]

PMID: 17097639

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Project description:The PINK1 (phosphatase and tensin homologue-induced putative kinase 1)/Parkin-dependent mitochondrial quality control pathway mediates the clearance of damaged organelles, but appears to be disrupted in Parkinson's disease (PD) [Springer and Kahle (2011) Autophagy 7, 266-278]. Upon mitochondrial stress, PINK1 activates the E3 ubiquitin (Ub) ligase Parkin through phosphorylation of the Ub-like (UBL) domain of Parkin and of the small modifier Ub itself at a conserved residue [Sauvé and Gehring (2014) Cell Res. 24, 1025-1026]. Recently resolved partial crystal structures of Parkin showed a 'closed', auto-inhibited conformation, consistent with its notoriously weak enzymatic activity at steady state [Wauer and Komander (2013) EMBO J. 32, 2099-2112; Riley et al. (2013) Nat. Commun. 4, 1982; Trempe et al. (2013) Science 340, 1451-1455; Spratt et al. (2013) Nat. Commun. 4, 1983]. It has thus become clear that Parkin must undergo major structural rearrangements in order to unleash its catalytic functions. Recent published findings derived from X-ray structures and molecular modelling present a complete structural model of human Parkin at an all-atom resolution [Caulfield et al. (2014) PLoS Comput. Biol. 10, e1003935]. The results of the combined in silico simulations-based and experimental assay-based study indicates that PINK1-dependent Ser65 phosphorylation of Parkin is required for its activation and triggering of 'opening' conformations. Indeed, the obtained structures showed a sequential release of Parkin's intertwined domains and allowed docking of an Ub-charged E2 coenzyme, which could enable its enzymatic activity. In addition, using cell-based screening, select E2 enzymes that redundantly, cooperatively or antagonistically regulate Parkin's activation and/or enzymatic functions at different stages of the mitochondrial autophagy (mitophagy) process were identified [Fiesel et al. (2014) J. Cell Sci. 127, 3488-3504]. Other work that aims to pin-point the particular pathogenic dysfunctions of Parkin mis-sense mutations have been recently disseminated (Fabienne C. Fiesel, Thomas R. Caulfield, Elisabeth L. Moussaud-Lamodiere, Daniel F.A.R. Dourado, Kotaro Ogaki, Owen A. Ross, Samuel C. Flores, and Wolfdieter Springer, submitted). Such a structure-function approach provides the basis for the dissection of Parkin's regulation and a targeted drug design to identify small-molecule activators of this neuroprotective E3 Ub ligase.

Dataset Information

Parkin is an E3 ubiquitin-ligase for normal and mutant ataxin-2 and prevents ataxin-2-induced cell death.

Publications

Parkin is an E3 ubiquitin-ligase for normal and mutant ataxin-2 and prevents ataxin-2-induced cell death.

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