Drosophila histone deacetylase 6 protects dopaminergic neurons against {alpha}-synuclein toxicity by promoting inclusion formation.
Parkinson's disease (PD) is associated with progressive degeneration of dopaminergic (DA) neurons. We report for the first time that the Drosophila histone deacetylase 6 (dHDAC6) plays a critical role in the protection of DA neurons and the formation of alpha-synuclein inclusions by using a Drosophila PD model constructed by ectopic expression of human alpha-synuclein. Depletion of dHDAC6 significantly enhances the effects caused by ectopic expression of alpha-synuclein, namely, loss of DA neurons, retinal degeneration, and locomotor dysfunction. Expression of alpha-synuclein in the DA neurons leads to fewer inclusions in the brains of dHDAC6 mutant flies than in wild-type flies. Conversely, overexpression of dHDAC6 is able to suppress the alpha-synuclein-induced DA neuron loss and retinal degeneration and promote inclusion formation. Furthermore, mutation of dHDAC6 reinforces the accumulation of oligomers that are suggested to be a toxic form of alpha-synuclein. We propose that alpha-synuclein inclusion formation in the presence of dHDAC6 protects DA neurons from being damaged by oligomers, which may uncover a common mechanism for synucleinopathies.
Du
Guiping
G
National Laboratory of Macromolecules and State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Liu
Xiang
X
Chen
Xinping
X
Song
Mei
M
Yan
Yan
Y
Jiao
Renjie
R
Wang
Chih-Chen
CC
D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000201:enzymology* / Q000235:genetics; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
D029721:Drosophila Proteins; D051844:alpha-Synuclein; C425683:HDAC6 protein, Drosophila; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D004298:Dopamine
Nat Neurosci. 2005 May;8(5):657-63
15834418
J Neurochem. 2002 Nov;83(4):846-54
12421356
J Neurol Neurosurg Psychiatry. 2008 Apr;79(4):368-76
18344392
J Neurosci. 2007 Mar 21;27(12):3338-46
17376994
Science. 2002 Jun 14;296(5575):1991-5
12065827
Int J Clin Exp Pathol. 2008 Jan 01;1(3):217-31
18784814
Nature. 2000 Mar 23;404(6776):394-8
10746727
Science. 1997 Jun 27;276(5321):2045-7
9197268
Genes Dev. 2007 Sep 1;21(17):2172-81
17785525
Learn Mem. 2008 Feb 28;15(3):133-42
18310460
Science. 2003 Oct 31;302(5646):841
14593171
Am J Pathol. 2009 Aug;175(2):736-47
19628769
Science. 2000 Jun 16;288(5473):2013-8
10856208
Annu Rev Biochem. 2005;74:29-52
15952880
PLoS One. 2008 Apr 02;3(4):e1867
18382657
Neurobiol Dis. 2008 Apr;30(1):65-73
18243716
J Am Chem Soc. 2009 Dec 2;131(47):17482-9
19888725
Nat Genet. 1998 Feb;18(2):106-8
9462735
Brain Res. 2007 Mar 30;1139:220-5
17280646
Genome Res. 2008 Jan;18(1):123-36
18042644
Nature. 2007 Jun 14;447(7146):859-63
17568747
Science. 2007 Jul 27;317(5837):516-9
17588900
J Neurosci. 2004 Dec 1;24(48):10993-8
15574749
Science. 1996 Nov 15;274(5290):1197-9
8895469
Cell. 2003 Dec 12;115(6):727-38
14675537
Science. 2000 Feb 18;287(5456):1265-9
10678833
Ann Neurol. 1998 Sep;44(3):415-22
9749615
Nature. 2004 Oct 14;431(7010):805-10
15483602
Hum Mol Genet. 2003 Apr 1;12(7):749-57
12651870
Mol Cell Biol. 2006 Mar;26(6):2286-96
16508004
J Mol Biol. 2006 Dec 1;364(3):323-36
17010992
EMBO J. 2006 Jul 26;25(14):3357-66
16810319
N Engl J Med. 1998 Oct 15;339(16):1130-43
9770561
Neuron. 2003 Feb 20;37(4):583-95
12597857
EMBO J. 2009 Oct 21;28(20):3256-68
19745811
Nature. 1998 Apr 9;392(6676):605-8
9560156
Science. 2003 Apr 18;300(5618):486-9
12702875
Oncogene. 2007 Aug 13;26(37):5468-76
17694087
Genesis. 2002 Sep-Oct;34(1-2):80-2
12324954
J Neurosci. 2006 Sep 6;26(36):9227-38
16957079
Hum Mol Genet. 2003 Jun 1;12(11):1223-31
12761037
Nat Med. 1998 Nov;4(11):1318-20
9809558
Science. 2002 Feb 1;295(5556):865-8
11823645
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2884-9
12601150
J Neurobiol. 2003 Mar;54(4):618-27
12555273
Nature. 2002 Jul 18;418(6895):291
12124613