Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3?

被引：79

作者：

Alves, Sandro ^{[1
,2
,4
,5
]}

Nascimento-Ferreira, Isabel ^{[1
,2
]}

Dufour, Noelle ^{[4
,5
,6
]}

Hassig, Raymonde ^{[4
,5
,6
]}

Auregan, Gwennaelle ^{[4
,5
,6
]}

Nobrega, Clevio ^{[1
]}

Brouillet, Emmanuel ^{[4
,5
,6
]}

Hantraye, Philippe ^{[4
,5
,6
]}

Pedroso de Lima, Maria C. ^{[1
,3
]}

Deglon, Nicole ^{[4
,5
,6
]}

de Almeida, Luis Pereira ^{[1
,2
]}

机构：

[1] Univ Coimbra, Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal

[2] Univ Coimbra, Fac Pharm, P-3004517 Coimbra, Portugal

[3] Univ Coimbra, Fac Sci & Technol, P-3004517 Coimbra, Portugal

[4] CEA, Inst Mol Imaging I2BM, Orsay, France

[5] Mol Imaging Res Ctr MIRCen, Orsay, France

[6] CNRS, URA2210, F-91405 Orsay, France

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 12期

关键词：

MUTANT HUNTINGTIN; POLYGLUTAMINE PROTEINS; RNA INTERFERENCE; GENE-PRODUCT; INTRANUCLEAR INCLUSIONS; EXPANDED POLYGLUTAMINE; MEDIATED DELIVERY; EXPRESSION; NEURODEGENERATION; NEUROPATHOLOGY;

D O I：

10.1093/hmg/ddq111

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) is a fatal, autosomal dominant disorder caused by a cytosine-adenine-guanine expansion in the coding region of the MJD1 gene. RNA interference has potential as a therapeutic approach but raises the issue of the role of wild-type ataxin-3 (WT ATX3) in MJD and of whether the expression of the wild-type protein must be maintained. To address this issue, we both overexpressed and silenced WT ATX3 in a rat model of MJD. We showed that (i) overexpression of WT ATX3 did not protect against MJD pathology, (ii) knockdown of WT ATX3 did not aggravate MJD pathology and that (iii) non-allele-specific silencing of ataxin-3 strongly reduced neuropathology in a rat model of MJD. Our findings indicate that therapeutic strategies involving non-allele-specific silencing to treat MJD patients may be safe and effective.

引用

页码：2380 / 2394

页数：15

共 74 条

[21] Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado-Joseph disease brains [J].

Fujigasaki, H ;

Uchihara, T ;

Koyano, S ;

Iwabuchi, K ;

Yagishita, S ;

Makifuchi, T ;

Nakamura, A ;

Ishida, K ;

Toru, S ;

Hirai, S ;

Ishikawa, K ;

Tanabe, T ;

Mizusawa, H .

EXPERIMENTAL NEUROLOGY, 2000, 165 (02) :248-256

[22] Preferential recruitment of ataxin-3 independent of expanded polyglutamine: an immunohistochemical study on Marinesco bodies [J].

Fujigasaki, H ;

Uchihara, T ;

Takahashi, J ;

Matsushita, H ;

Nakamura, A ;

Koyano, S ;

Iwabuchi, K ;

Hirai, S ;

Mizusawa, H .

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2001, 71 (04) :518-520

[23] Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins [J].

Gaspar, C ;

LopesCendes, I ;

DeStefano, AL ;

Maciel, P ;

Silveira, I ;

Coutinho, P ;

MacLeod, P ;

Sequeiros, J ;

Farrer, LA ;

Rouleau, GA .

HUMAN GENETICS, 1996, 98 (05) :620-624

[24] Ancestral origins of the Machado-Joseph disease mutation: A worldwide haplotype study [J].

Gaspar, C ;

Lopes-Cendes, I ;

Hayes, S ;

Goto, J ;

Arvidsson, K ;

Dias, A ;

Silveira, I ;

Maciel, P ;

Coutinho, P ;

Lima, M ;

Zhou, YX ;

Soong, BW ;

Watanabe, M ;

Giunti, P ;

Stevanin, G ;

Riess, O ;

Sasaki, H ;

Hsieh, M ;

Nicholson, GA ;

Brunt, E ;

Higgins, JJ ;

Lauritzen, M ;

Tranebjaerg, L ;

Volpini, V ;

Wood, N ;

Ranum, L ;

Tsuji, S ;

Brice, A ;

Sequeiros, J ;

Rouleau, GA .

AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (02) :523-528

[25] Spinocerebellar ataxia type 3 phenotypically resembling Parkinson disease in a black family [J].

Gwinn-Hardy, K ;

Singleton, A ;

O'Suilleabhain, P ;

Boss, M ;

Nicholl, D ;

Adam, A ;

Hussey, J ;

Critchley, P ;

Hardy, J ;

Farrer, M .

ARCHIVES OF NEUROLOGY, 2001, 58 (02) :296-299

[26] RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model [J].

Harper, SQ ;

Staber, PD ;

He, XH ;

Eliason, SL ;

Martins, IH ;

Mao, QW ;

Yang, L ;

Kotin, RM ;

Paulson, HL ;

Davidson, BL .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (16) :5820-5825

[27] Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus [J].

Hottinger, AF ;

Azzouz, M ;

Déglon, N ;

Aebischer, P ;

Zurn, AD .

JOURNAL OF NEUROSCIENCE, 2000, 20 (15) :5587-5593

[28] Dopamine Gene Therapy for Parkinson's Disease in a Nonhuman Primate Without Associated Dyskinesia [J].

Jarraya, Bechir ;

Boulet, Sabrina ;

Ralph, G. Scott ;

Jan, Caroline ;

Bonvento, Gilles ;

Azzouz, Mimoun ;

Miskin, James E. ;

Shin, Masahiro ;

Delzescaux, Thierry ;

Drouot, Xavier ;

Herard, Anne-Sophie ;

Day, Denise M. ;

Brouillet, Emmanuel ;

Kingsman, Susan M. ;

Hantraye, Philippe ;

Mitrophanous, Kyriacos A. ;

Mazarakis, Nicholas D. ;

Palfi, Stephane .

SCIENCE TRANSLATIONAL MEDICINE, 2009, 1 (02)

[29] CAG EXPANSIONS IN A NOVEL GENE FOR MACHADO-JOSEPH DISEASE AT CHROMOSOME 14Q32.1 [J].

KAWAGUCHI, Y ;

OKAMOTO, T ;

TANIWAKI, M ;

AIZAWA, M ;

INOUE, M ;

KATAYAMA, S ;

KAWAKAMI, H ;

NAKAMURA, S ;

NISHIMURA, M ;

AKIGUCHI, I ;

KIMURA, J ;

NARUMIYA, S ;

KAKIZUKA, A .

NATURE GENETICS, 1994, 8 (03) :221-228

[30] Intranuclear aggregation of nonexpanded ataxin-3 in Marinesco bodies of the nonhuman primate substantia nigra [J].

Kettner, M ;

Willwohl, D ;

Hubbard, GB ;

Rüb, U ;

Dick, EJ ;

Cox, AB ;

Trottier, Y ;

Auburger, G ;

Braak, H ;

Schultz, C .

EXPERIMENTAL NEUROLOGY, 2002, 176 (01) :117-121

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