title: Ataxin-3 and its e3 partners: implications for machado-joseph disease.
abstract: Machado-Joseph disease (MJD) is the most common dominant inherited ataxia worldwide, caused by an unstable CAG trinucleotide expansion mutation within the SCA3 gene resulting in an expanded polyglutamine tract within the ataxin-3 protein. Ataxin-3 functions as a deubiquitinating enzyme (DUB), within the Ub system and whilst many DUBs are known to partner with and deubiquitinate specific E3-Ub ligases, ataxin-3 had no identified E3 partner until recent studies implicated parkin and CHIP, two neuroprotective E3 ligases. MJD often presents with symptoms of Parkinson disease (PD), which led to identification of parkin as a novel E3-Ub ligase whose activity was regulated by ataxin-3-mediated deubiquitination. Findings from these studies also revealed an unexpected convergence upon the E2-Ub-conjugating enzyme in the regulation of an E3/DUBenzyme pair. Moreover, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of the Parkinsonian features in MJD. In addition to parkin, the U-box E3 ligase CHIP, a neuroprotective E3 implicated in protein quality control, was identified as a second E3 partner of ataxin-3, with ataxin-3 regulating the ability of CHIP to ubiquitinate itself. Indeed, ataxin-3 not only deubiquitinated CHIP, but also trimmed Ub conjugates on CHIP substrates, thereby regulating the length of Ub chains. Interestingly, when expanded ataxin-3 was present, CHIP levels were also reduced in the brains of MJD transgenic mice, raising the possibility that loss of one or both E3 partners may be a contributing factor in the pathogenesis of SCA3. In this review we discuss the implications from these studies and describe the importance of these findings in helping us understand the molecular processes involved in SCA3 and other neurodegenerative disorders.
authors: Department of Neurology and Neurosurgery, Centre for Neuronal Survival and McGill Parkinson Program, Montreal Neurological Institute, McGill University Montreal, QC, Canada.
authors: Thomas M
authors: TM
authors: Durcan
authors: Edward A
authors: EA
authors: Fon
keywords: CHIP; Machado–Joseph disease; Parkinson’s disease; ataxin-3; parkin; polyglutamine expansion
references: Hum Mol Genet. 2011 Jan 1;20(1):141-54
references: 20940148
references: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4330-5
references: 15767577
references: J Biol Chem. 2012 Jan 20;287(4):2317-27
references: 22069321
references: J Neurosci Res. 2009 Jun;87(8):1884-91
references: 19185026
references: Biochim Biophys Acta. 2012 Feb;1822(2):139-49
references: 22037589
references: Arch Neurol. 2001 Feb;58(2):296-9
references: 11176969
references: Neurodegener Dis. 2013;11(4):206-14
references: 22832131
references: J Cell Biol. 2013 Jan 21;200(2):163-72
references: 23319602
references: J Biol Chem. 2005 Mar 25;280(12):11635-40
references: 15664989
references: Nat Genet. 2000 Jul;25(3):302-5
references: 10888878
references: Biochem Biophys Res Commun. 2010 Sep 24;400(3):389-95
references: 20800574
references: J Virol. 2000 Jul;74(14):6408-17
references: 10864652
references: Nature. 2011 Jun 2;474(7349):105-8
references: 21532592
references: J Biol Chem. 2010 Dec 10;285(50):39303-13
references: 20943656
references: Traffic. 2008 Jul;9(7):1130-45
references: 18410486
references: J Biol Chem. 2012 Aug 17;287(34):28576-85
references: 22761419
references: BMC Neurol. 2011 Oct 24;11:131
references: 22023810
references: Nature. 2004 Aug 5;430(7000):694-9
references: 15258597
references: Mol Cell Biol. 2003 Sep;23(18):6469-83
references: 12944474
references: Exp Neurol. 2000 Oct;165(2):248-56
references: 10993685
references: J Cell Biol. 2008 Dec 1;183(5):795-803
references: 19029340
references: Neuron. 1997 Aug;19(2):333-44
references: 9292723
references: Mitochondrion. 2011 Jan;11(1):139-46
references: 20851218
references: J Biol Chem. 2001 Nov 30;276(48):44889-97
references: 11572863
references: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8892-7
references: 12857950
references: Hum Mol Genet. 2003 Nov 1;12(21):2845-52
references: 12944423
references: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10493-8
references: 16020535
references: J Biol Chem. 2008 Sep 26;283(39):26436-43
references: 18599482
references: Mol Cell. 2011 Aug 19;43(4):599-612
references: 21855799
references: Neurobiol Dis. 2008 May;30(2):190-200
references: 18353661
references: Biochim Biophys Acta. 2012 Feb;1822(2):101-10
references: 22080977
references: Hum Mol Genet. 2009 Jan 1;18(1):27-42
references: 18824496
references: J Biol Chem. 2012 Jan 2;287(1):531-541
references: 22081612
references: J Biol Chem. 2003 Jun 13;278(24):22044-55
references: 12676955
references: Cell. 2002 Oct 18;111(2):209-18
references: 12408865
references: Biochimie. 2008 Feb;90(2):270-83
references: 17961905
references: Autophagy. 2011 Feb;7(2):233-4
references: 21116127
references: Hum Mol Genet. 2003 Dec 1;12(23):3195-205
references: 14559776
references: Nat Genet. 1994 Nov;8(3):221-8
references: 7874163
references: Nature. 2011 Nov 23;480(7378):543-6
references: 22113611