title: Striatal pre-enkephalin overexpression improves Huntington's disease symptoms in the R6/2 mouse model of Huntington's disease.
abstract: The reduction of pre-enkephalin (pENK) mRNA expression might be an early sign of striatal neuronal dysfunction in Huntington's disease (HD), due to mutated huntingtin protein. Indeed, striatopallidal (pENK-containing) neurodegeneration occurs at earlier stage of the disease, compare to the loss of striatonigral neurons. However, no data are available about the functional role of striatal pENK in HD. According to the neuroprotective properties of opioids that have been recognized recently, the objective of this study was to investigate whether striatal overexpression of pENK at early stage of HD can improve motor dysfunction, and/or reduce striatal neuronal loss in the R6/2 transgenic mouse model of HD. To achieve this goal recombinant adeno-associated-virus (rAAV2)-containing green fluorescence protein (GFP)-pENK was injected bilaterally in the striatum of R6/2 mice at 5 weeks old to overexpress opioid peptide pENK. Striatal injection of rAAV2-GFP was used as a control. Different behavioral tests were carried out before and/or after striatal injections of rAAV2. The animals were euthanized at 10 weeks old. Our results demonstrate that striatal overexpression of pENK had beneficial effects on behavioral symptoms of HD in R6/2 by: delaying the onset of decline in muscular force; reduction of clasping; improvement of fast motor activity, short-term memory and recognition; as well as normalization of anxiety-like behavior. The improvement of behavioral dysfunction in R6/2 mice having received rAAV2-GFP-pENK associated with upregulation of striatal pENK mRNA; the increased level of enkephalin peptide in the striatum, globus pallidus and substantia nigra; as well as the slight increase in the number of striatal neurons compared with other groups of R6/2. Accordingly, we suggest that at early stage of HD upregulation of striatal enkephalin might play a key role at attenuating illness symptoms.
authors.affiliation: Axe Neurosciences, Centre de recherche du CHU de Québec, CHUL, Québec, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bissonnette
authors.forename: Mylène
authors.initials: M
authors.lastname: Vaillancourt
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Hébert
authors.forename: Guy
authors.initials: G
authors.lastname: Drolet
authors.forename: Pershia
authors.initials: P
authors.lastname: Samadi
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D004745:Enkephalins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D005917:Globus Pallidus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy*; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: D004745:Enkephalins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011957:Receptors, Opioid; D049452:Green Fluorescent Proteins
references.citation: Learn Mem. 2011 Jun 21;18(7):459-74
references.pmid: 21693634
references.citation: J Comp Neurol. 1997 Dec 15;389(2):193-211
references.pmid: 9416916
references.citation: Trends Neurosci. 2003 Apr;26(4):215-21
references.pmid: 12689773
references.citation: Neuroreport. 2000 Apr 7;11(5):923-6
references.pmid: 10790856
references.citation: Peptides. 2009 Dec;30(12):2432-79
references.pmid: 19793543
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1669-74
references.pmid: 21205893
references.citation: Trends Neurosci. 2009 May;32(5):249-56
references.pmid: 19307031
references.citation: J Chem Neuroanat. 2004 Jun;27(3):143-64
references.pmid: 15183201
references.citation: Hum Mol Genet. 2011 Nov 1;20(21):4232-47
references.pmid: 21835884
references.citation: Proc Natl Acad Sci U S A. 1988 Aug;85(15):5733-7
references.pmid: 2456581
references.citation: J Neurosci. 2007 Nov 21;27(47):12908-15
references.pmid: 18032664
references.citation: Neuron. 1995 Sep;15(3):493-6
references.pmid: 7546729
references.citation: Cell. 1998 Oct 2;95(1):55-66
references.pmid: 9778247
references.citation: Trends Neurosci. 2000 Oct;23(10 Suppl):S20-7
references.pmid: 11052216
references.citation: Neurosurgery. 2010 Oct;67(4):1073-9; discussion1080
references.pmid: 20881571
references.citation: J Neurosci. 2001 May 1;21(9):3242-50
references.pmid: 11312309
references.citation: Brain Res. 1998 Sep 14;805(1-2):234-40
references.pmid: 9733972
references.citation: Genes Brain Behav. 2011 Apr;10(3):299-308
references.pmid: 21091868
references.citation: J Comp Neurol. 1994 Jul 1;345(1):46-68
references.pmid: 8089277
references.citation: Annu Rev Biochem. 2004;73:953-90
references.pmid: 15189164
references.citation: Neurobiol Dis. 2001 Apr;8(2):343-50
references.pmid: 11300729
references.citation: Exp Neurol. 2004 Mar;186(1):46-58
references.pmid: 14980809
references.citation: J Neurosci. 2009 Sep 16;29(37):11550-9
references.pmid: 19759302
references.citation: Cell Transplant. 2001 Jan-Feb;10(1):53-8
references.pmid: 11294472
references.citation: Brain Res. 1984 Dec 3;323(1):21-9
references.pmid: 6098334
references.citation: Learn Mem. 2004 Jul-Aug;11(4):459-63
references.pmid: 15286184
references.citation: J Comp Neurol. 2005 Oct 3;490(4):354-70
references.pmid: 16127709
references.citation: Ann N Y Acad Sci. 2005 Aug;1053:107-20
references.pmid: 16179514
references.citation: Eur J Neurosci. 2013 Apr;37(8):1357-67
references.pmid: 23368426
references.citation: Neuron. 1993 Nov;11(5):985-93
references.pmid: 8240819
references.citation: J Physiol. 2007 Dec 15;585(Pt 3):817-31
references.pmid: 17947312
references.citation: Physiol Rev. 2001 Jan;81(1):299-343
references.pmid: 11152760
references.citation: Prog Neurobiol. 2007 Apr;81(5-6):253-71
references.pmid: 17169479
references.citation: J Neurol. 2004 Aug;251(8):935-42
references.pmid: 15316797
references.citation: J Cereb Blood Flow Metab. 1997 Sep;17(9):943-9
references.pmid: 9307607
references.citation: Brain Res. 2004 Sep 3;1019(1-2):246-54
references.pmid: 15306259
references.citation: Neurosci Lett. 2006 Oct 2;406(1-2):138-41
references.pmid: 16905252
references.citation: J Biol Chem. 2007 Aug 24;282(34):24554-62
references.pmid: 17565993
references.citation: Brain Res. 2009 Feb 3;1252:183-91
references.pmid: 19056363
references.citation: J Neurosci. 1999 Feb 15;19(4):1189-202
references.pmid: 9952397
references.citation: Neuropharmacology. 2005 Aug;49(2):165-73
references.pmid: 15996565
references.citation: Neurosci Lett. 2002 Oct 25;332(1):5-8
references.pmid: 12377371
references.citation: Curr Pharm Des. 2005;11(10):1343-50
references.pmid: 15853689
references.citation: Ann N Y Acad Sci. 2010 Jun;1198:260-70
references.pmid: 20536941
references.citation: Genes Brain Behav. 2013 Feb;12(1):108-24
references.pmid: 23006318
references.citation: Mov Disord. 2002 Jul;17(4):748-57
references.pmid: 12210870
references.citation: J Comp Neurol. 1997 Jan 6;377(1):85-94
references.pmid: 8986874
references.citation: Neuroscience. 2008 Apr 22;153(1):329-37
references.pmid: 18353560
references.citation: Nat Neurosci. 2006 Feb;9(2):251-9
references.pmid: 16415865
references.citation: Brain Behav Immun. 2012 Aug;26(6):880-5
references.pmid: 22401992
references.citation: Neuron. 2010 Jan 28;65(2):178-90
references.pmid: 20152125
references.citation: J Biol Chem. 2005 Apr 22;280(16):16208-18
references.pmid: 15687501
references.citation: J Neurochem. 2000 Oct;75(4):1694-702
references.pmid: 10987852
references.citation: Neurobiol Dis. 2008 Mar;29(3):409-21
references.pmid: 18063376
references.citation: Trends Pharmacol Sci. 2006 Oct;27(10):512-7
references.pmid: 16908075
references.citation: J Neurophysiol. 2000 Jun;83(6):3366-76
references.pmid: 10848555
references.citation: CNS Neurosci Ther. 2010 Jun;16(3):163-78
references.pmid: 20406248
references.citation: Methods. 2002 Oct;28(2):158-67
references.pmid: 12413414
references.citation: Cell. 2005 Dec 29;123(7):1241-53
references.pmid: 16377565
references.citation: J Neurosci. 2005 Apr 20;25(16):4169-80
references.pmid: 15843620
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2509-14
references.pmid: 9482916
references.citation: Ann Neurol. 1991 Oct;30(4):542-9
references.pmid: 1838677
references.citation: Cell. 1993 Mar 26;72(6):971-83
references.pmid: 8458085
references.citation: Nat Rev Neurosci. 2004 May;5(5):373-84
references.pmid: 15100720
references.citation: J Neurosci Methods. 2010 Apr 30;188(1):45-52
references.pmid: 20138914
references.citation: Neuron. 2011 Feb 10;69(3):423-35
references.pmid: 21315254
references.citation: J Biol Chem. 1984 Nov 25;259(22):14301-8
references.pmid: 6548748
references.citation: Exp Neurol. 2004 Mar;186(1):1-5
references.pmid: 14980805
references.citation: J Neurosci. 1992 Jan;12(1):356-61
references.pmid: 1309576
references.citation: Eur J Pharmacol. 2011 May 11;658(2-3):140-4
references.pmid: 21349267
references.citation: Exp Neurol. 2000 Apr;162(2):328-42
references.pmid: 10739639
references.citation: J Biol Chem. 1998 Sep 4;273(36):23534-41
references.pmid: 9722592
references.citation: Neuroscience. 1999;88(4):1093-135
references.pmid: 10336124
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10458-63
references.pmid: 15240883
references.citation: J Neurosci Res. 2002 Jun 15;68(6):716-29
references.pmid: 12111832
references.citation: Neurobiol Dis. 2012 Dec;48(3):488-94
references.pmid: 22813864
references.citation: J Neurosci. 2004 Sep 22;24(38):8289-99
references.pmid: 15385612
references.citation: BMC Biol. 2009 Aug 26;7:55
references.pmid: 19709398
references.citation: Neurobiol Dis. 2002 Dec;11(3):369-85
references.pmid: 12586547
references.citation: Neurosci Lett. 2007 Aug 16;423(2):113-7
references.pmid: 17689189
references.citation: Neurosci Lett. 2003 Mar 13;339(1):53-6
references.pmid: 12618299
references.citation: Neuron. 2009 Apr 30;62(2):218-29
references.pmid: 19409267