SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types

被引:80
作者
Yvert, G
Lindenberg, KS
Devys, D
Helmlinger, D
Landwehrmeyer, GB
Mandel, JL
机构
[1] ULP, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France
[2] CU Strasbourg, Strasbourg, France
[3] Univ Ulm, Dept Neurol, D-89075 Ulm, Germany
关键词
D O I
10.1093/hmg/10.16.1679
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
Accumulation of expanded polyglutamine proteins and selective pattern of neuronal loss are hallmarks of at least eight neurodegenerative disorders, including spinocerebellar ataxia type 7 (SCA7). We previously described SCA7 mice displaying neurodegeneration with progressive ataxin-7 accumulation in two cell types affected in the human pathology. We describe here a new transgenic model with a more widespread expression of mutant ataxin-7, including neuronal cell types unaffected in SCA7. In these mice a similar handling of mutant ataxin-7, including a cytoplasm to nucleus translocation and accumulation of N-terminal fragments, was observed in all neuronal populations studied. An extensive screen for chaperones, proteasomal subunits and transcription factors sequestered in nuclear inclusions (NIs) disclosed no pattern unique to neurons undergoing degeneration in SCA7. In particular, we found that the mouse TAF(parallel to)30 subunit of the TFIID initiation complex is markedly accumulated in NIs, even though this protein does not contain a polyglutamine stretch. A striking discrepancy between mRNA and ataxin-7 levels in transgenic mice expressing the wild-type protein but not in those expressing the mutant one, indicates a selective stabilization of mutant ataxin-7, both in this model and the P7E/N model described previously. These mice therefore provide in vivo evidence that the polyglutamine expansion mutation can stabilize its target protein.
引用
收藏
页码:1679 / 1692
页数:14
相关论文
共 40 条
  • [1] STABILITY OF AN EXPANDED TRINUCLEOTIDE REPEAT IN THE ANDROGEN RECEPTOR GENE IN TRANSGENIC MICE
    BINGHAM, PM
    SCOTT, MO
    WANG, SP
    MCPHAUL, MJ
    WILSON, EM
    GARBERN, JY
    MERRY, DE
    FISCHBECK, KH
    [J]. NATURE GENETICS, 1995, 9 (02) : 191 - 196
  • [2] Aberrant interactions of transcriptional repressor proteins with the Huntington's disease gene product, huntingtin
    Boutell, JM
    Thomas, P
    Neal, JW
    Weston, VJ
    Duce, J
    Harper, PS
    Jones, AL
    [J]. HUMAN MOLECULAR GENETICS, 1999, 8 (09) : 1647 - 1655
  • [3] Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice
    Cummings, CJ
    Reinstein, E
    Sun, YL
    Antalffy, B
    Jiang, YH
    Ciechanover, A
    Orr, HT
    Beaudet, AL
    Zoghbi, HY
    [J]. NEURON, 1999, 24 (04) : 879 - 892
  • [4] Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion
    David, G
    Abbas, N
    Stevanin, G
    Durr, A
    Yvert, G
    Cancel, G
    Weber, C
    Imbert, G
    Saudou, F
    Antoniou, E
    Drabkin, H
    Gemmill, R
    Giunti, P
    Benomar, A
    Wood, N
    Ruberg, M
    Agid, Y
    Mandel, JL
    Brice, A
    [J]. NATURE GENETICS, 1997, 17 (01) : 65 - 70
  • [5] DELIDOW BC, 1993, POLYM CHAIN REACTION
  • [6] Increased amyloid-beta 42(43) in brains of mice expressing mutant presenilin 1
    Duff, K
    Eckman, C
    Zehr, C
    Yu, X
    Prada, CM
    Pereztur, J
    Hutton, M
    Buee, L
    Harigaya, Y
    Yager, D
    Morgan, D
    Gordon, MN
    Holcomb, L
    Refolo, L
    Zenk, B
    Hardy, J
    Younkin, S
    [J]. NATURE, 1996, 383 (6602) : 710 - 713
  • [7] Identification of genes that modify ataxin-1-induced neurodegeneration
    Fernandez-Funez, P
    Nino-Rosales, ML
    de Gouyon, B
    She, WC
    Luchak, JM
    Martinez, P
    Turiegano, E
    Benito, J
    Capovilla, M
    Skinner, PJ
    McCall, A
    Canal, I
    Orr, HT
    Zoghbi, HY
    Botas, J
    [J]. NATURE, 2000, 408 (6808) : 101 - 106
  • [8] ALZHEIMER-TYPE NEUROPATHOLOGY IN TRANSGENIC MICE OVEREXPRESSING V717F BETA-AMYLOID PRECURSOR PROTEIN
    GAMES, D
    ADAMS, D
    ALESSANDRINI, R
    BARBOUR, R
    BERTHELETTE, P
    BLACKWELL, C
    CARR, T
    CLEMENS, J
    DONALDSON, T
    GILLESPIE, F
    GUIDO, T
    HAGOPIAN, S
    JOHNSONWOOD, K
    KHAN, K
    LEE, M
    LEIBOWITZ, P
    LIEBERBURG, I
    LITTLE, S
    MASLIAH, E
    MCCONLOGUE, L
    MONTOYAZAVALA, M
    MUCKE, L
    PAGANINI, L
    PENNIMAN, E
    POWER, M
    SCHENK, D
    SEUBERT, P
    SNYDER, B
    SORIANO, F
    TAN, H
    VITALE, J
    WADSWORTH, S
    WOLOZIN, B
    ZHAO, J
    [J]. NATURE, 1995, 373 (6514) : 523 - 527
  • [9] AUTOSOMAL-DOMINANT CEREBELLAR-ATAXIA WITH RETINAL DEGENERATION - CLINICAL, NEUROPATHOLOGIC, AND GENETIC-ANALYSIS OF A LARGE KINDRED
    GOUW, LG
    DIGRE, KB
    HARRIS, CP
    HAINES, JH
    PTACEK, LJ
    [J]. NEUROLOGY, 1994, 44 (08) : 1441 - 1447
  • [10] Gutekunst CA, 1999, J NEUROSCI, V19, P2522