title: Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivo.
abstract: An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/α-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human α-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by α-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies.
authors: Laboratory of Molecular and Chemical Biology of Neurodegeneration and Neurodegenerative Disease Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors: Abid
authors: A
authors: Oueslati
authors: Bernard L
authors: BL
authors: Schneider
authors: Patrick
authors: P
authors: Aebischer
authors: Hilal A
authors: HA
authors: Lashuel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D010300:Parkinson Disease / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; C530504:Plk2 protein, rat
keywords: adeno-associated virus; animal model; serum inducible kinase
references: Acta Neuropathol. 2012 May;123(5):653-69
references: 22361813
references: J Neurosci. 2010 Mar 3;30(9):3184-98
references: 20203178
references: Oncogene. 2005 Jan 10;24(2):292-8
references: 15640845
references: EMBO Rep. 2002 Jun;3(6):583-8
references: 12034752
references: J Neurochem. 2009 Aug;110(3):1005-13
references: 19493164
references: Oncogene. 2005 Jan 10;24(2):277-86
references: 15640843
references: Neuron. 2006 Oct 5;52(1):33-8
references: 17015225
references: J Biol Chem. 2006 Oct 6;281(40):29739-52
references: 16847063
references: Nat Rev Neurosci. 2013 Jan;14(1):38-48
references: 23254192
references: Nat Cell Biol. 2002 Feb;4(2):160-4
references: 11813001
references: Biochemistry. 2007 Aug 21;46(33):9551-63
references: 17655330
references: Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16119-24
references: 22988096
references: J Biol Chem. 2011 Oct 14;286(41):35863-35873
references: 21849493
references: J Neuropathol Exp Neurol. 2009 May;68(5):515-24
references: 19525899
references: Nat Rev Neurosci. 2006 Jan;7(1):30-40
references: 16371948
references: Curr Biol. 2004 Jul 13;14(13):1200-7
references: 15242618
references: Hum Mol Genet. 2012 Jun 1;21(11):2432-49
references: 22357655
references: Hum Mol Genet. 2009 Mar 1;18(5):872-87
references: 19074459
references: Trends Neurosci. 1999 Feb;22(2):51-61
references: 10092043
references: Nat Neurosci. 2005 May;8(5):657-63
references: 15834418
references: Oncogene. 2005 Jan 10;24(2):287-91
references: 15640844
references: J Neurosci. 2012 Feb 1;32(5):1536-44
references: 22302797
references: Nat Neurosci. 2010 Oct;13(10):1199-207
references: 20802490
references: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6469-73
references: 9600990
references: J Biol Chem. 2010 Dec 24;285(52):40732-44
references: 20959456
references: Science. 2003 Nov 21;302(5649):1368-73
references: 14576440
references: Acta Neuropathol. 2012 Aug;124(2):153-72
references: 22744791
references: Neuroscience. 2012 Jan 3;200:106-19
references: 22079575
references: Neuron. 2011 Mar 10;69(5):957-73
references: 21382555
references: Oncogene. 2005 Jan 10;24(2):267-76
references: 15640842
references: Adv Exp Med Biol. 2012;970:553-72
references: 22351072
references: Neuron. 2010 Jan 14;65(1):66-79
references: 20152114
references: N Engl J Med. 1998 Oct 8;339(15):1044-53
references: 9761807
references: J Neurosci. 2008 Jun 25;28(26):6583-91
references: 18579731
references: J Cell Sci. 2012 Feb 15;125(Pt 4):981-92
references: 22399798
references: J Neurosci. 2011 Nov 16;31(46):16884-94
references: 22090514
references: Science. 2010 Sep 24;329(5999):1663-7
references: 20798282
references: Nat Med. 2010 Jun;16(6):653-61
references: 20495568
references: N Engl J Med. 1998 Oct 15;339(16):1130-43
references: 9770561
references: Acta Neuropathol. 2011 Jun;121(6):695-704
references: 21400129
references: Mol Cell Proteomics. 2008 Nov;7(11):2123-37
references: 18614564
references: Neuron. 2008 May 22;58(4):571-83
references: 18498738
references: J Biol Chem. 2000 Aug 25;275(34):26515-22
references: 10852916
references: Biochem Biophys Res Commun. 2012 Feb 3;418(1):156-60
references: 22248692
references: Cell Death Dis. 2012 May 31;3:e315
references: 22647852
references: J Biol Chem. 2009 Jan 30;284(5):2598-2602
references: 19004816
references: Neurobiol Dis. 2009 Jul;35(1):32-41
references: 19348945
references: Biochem Biophys Res Commun. 2009 Jul 3;384(3):378-82
references: 19410557
references: Neurosci Lett. 2003 Jan 23;336(3):155-8
references: 12505616
references: PLoS One. 2010 Mar 24;5(3):e9849
references: 20352051
references: J Neurosci Res. 2011 Feb;89(2):231-47
references: 21162130
references: Cell Cycle. 2008 Nov 15;7(22):3548-55
references: 19001868
references: J Biol Chem. 2010 Jan 22;285(4):2807-22
references: 19889641
references: Neuroscience. 2009 Jun 2;160(4):796-804
references: 19272424
references: J Clin Invest. 2002 Nov;110(10):1429-39
references: 12438441
references: J Biol Chem. 2002 Dec 13;277(50):49071-6
references: 12377775
references: J Biol Chem. 2008 Jun 13;283(24):16895-905
references: 18343814
references: Neuron. 2011 Oct 6;72(1):57-71
references: 21982369
references: Nat Genet. 2009 Mar;41(3):308-15
references: 19182805