Differential distribution of the normal and mutated forms of huntingtin in the human brain

被引:37
作者
GourfinkelAn, I
Cancel, G
Trottier, Y
Devys, D
Tora, L
Lutz, Y
Imbert, G
Saudou, F
Stevanin, G
Agid, Y
Brice, A
Mandel, JL
Hirsch, EC
机构
[1] HOP LA PITIE SALPETRIERE,INSERM,U289,F-75651 PARIS 13,FRANCE
[2] UNIV STRASBOURG 1,CU STRASBOURG,INST GENET & BIOL MOL & CELLULAIRE,CNRS,INSERM,STRASBOURG,FRANCE
关键词
D O I
10.1002/ana.410420507
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Huntington's disease is an inherited disorder caused by expansion of a CAG trinucleotide repeat in the IT15 gene, which leads to expansion of a polyglutamine tract within the protein called huntingtin. Despite the characterization of the IT15 gene and the mutation involved in the disease, the normal function of huntingtin and the effects of the mutation on its function and on its neuronal location remain unknown. To study whether mutated huntingtin has the same neuronal distribution and intracellular location as normal huntingtin, we analyzed immunohistochemically both forms of this protein in the brain of 5 controls and 5 patients with Huntington's disease. We show that the distribution of mutated huntingtin is, like that of the normal form, heterogeneous throughout the brain, but is not limited to vulnerable neurons in Huntington's disease, supporting the hypothesis that the presence of the mutated huntingtin in a neuron is not in itself sufficient to lead to neuronal death. Moreover, whereas normal huntingtin is detected in some neuronal perikarya, nerve fibers, and nerve endings, the mutated form is observed in some neuronal perikarya and proximal nerve processes but is not detectable in nerve endings. Our results suggest that the expression or processing of the mutated huntingtin in perikarya and nerve endings differs quantitatively or qualitatively from the expression of the normal form in the same neuronal compartments.
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页码:712 / 719
页数:8
相关论文
共 41 条
  • [1] STRUCTURE AND EXPRESSION OF THE HUNTINGTONS-DISEASE GENE - EVIDENCE AGAINST SIMPLE INACTIVATION DUE TO AN EXPANDED CAG REPEAT
    AMBROSE, CM
    DUYAO, MP
    BARNES, G
    BATES, GP
    LIN, CS
    SRINIDHI, J
    BAXENDALE, S
    HUMMERICH, H
    LEHRACH, H
    ALTHERR, M
    WASMUTH, J
    BUCKLER, A
    CHURCH, D
    HOUSMAN, D
    BERKS, M
    MICKLEM, G
    DURBIN, R
    DODGE, A
    READ, A
    GUSELLA, J
    MACDONALD, ME
    [J]. SOMATIC CELL AND MOLECULAR GENETICS, 1994, 20 (01) : 27 - 38
  • [2] [Anonymous], 1991, HUNTINGTONS DIS
  • [3] CAG EXPANSION AFFECTS THE EXPRESSION OF MUTANT HUNTINGTIN IN THE HUNTINGTONS-DISEASE BRAIN
    ARONIN, N
    CHASE, K
    YOUNG, C
    SAPP, E
    SCHWARZ, C
    MATTA, N
    KORNREICH, R
    LANDWEHRMEYER, B
    BIRD, E
    BEAL, MF
    VONSATTEL, JP
    SMITH, T
    CARRAWAY, R
    BOYCE, FM
    YOUNG, AB
    PENNEY, JB
    DIFIGLIA, M
    [J]. NEURON, 1995, 15 (05) : 1193 - 1201
  • [4] Expansion of polyglutamine repeat in huntingtin leads to abnormal protein interactions involving calmodulin
    Bao, J
    Sharp, AH
    Wagster, MV
    Becher, M
    Schilling, G
    Ross, CA
    Dawson, VL
    Dawson, TM
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (10) : 5037 - 5042
  • [5] COMPARTMENTAL ORDERING OF CHOLINERGIC INNERVATION IN THE MEDIODORSAL NUCLEUS OF THE THALAMUS IN HUMAN BRAIN
    BRANDEL, JPA
    HIRSCH, EC
    HERSH, LB
    JAVOYAGID, F
    [J]. BRAIN RESEARCH, 1990, 515 (1-2) : 117 - 125
  • [6] Huntington and DRPLA proteins selectively interact with the enzyme GAPDH
    Burke, JR
    Enghild, JJ
    Martin, ME
    Jou, YS
    Myers, RM
    Roses, AD
    Vance, JM
    Strittmatter, WJ
    [J]. NATURE MEDICINE, 1996, 2 (03) : 347 - 350
  • [7] HUNTINGTIN IS A CYTOPLASMIC PROTEIN ASSOCIATED WITH VESICLES IN HUMAN AND RAT-BRAIN NEURONS
    DIFIGLIA, M
    SAPP, E
    CHASE, K
    SCHWARZ, C
    MELONI, A
    YOUNG, C
    MARTIN, E
    VONSATTEL, JP
    CARRAWAY, R
    REEVES, SA
    BOYCE, FM
    ARONIN, N
    [J]. NEURON, 1995, 14 (05) : 1075 - 1081
  • [8] INACTIVATION OF THE MOUSE HUNTINGTONS-DISEASE GENE HOMOLOG HDH
    DUYAO, MP
    AUERBACH, AB
    RYAN, A
    PERSICHETTI, F
    BARNES, GT
    MCNEIL, SM
    GE, P
    VONSATTEL, JP
    GUSELLA, JF
    JOYNER, AL
    MACDONALD, ME
    [J]. SCIENCE, 1995, 269 (5222) : 407 - 410
  • [9] SPARING OF ACETYLCHOLINESTERASE-CONTAINING STRIATAL NEURONS IN HUNTINGTONS-DISEASE
    FERRANTE, RJ
    BEAL, MF
    KOWALL, NW
    RICHARDSON, EP
    MARTIN, JB
    [J]. BRAIN RESEARCH, 1987, 411 (01) : 162 - 166
  • [10] SELECTIVE SPARING OF A CLASS OF STRIATAL NEURONS IN HUNTINGTONS-DISEASE
    FERRANTE, RJ
    KOWALL, NW
    BEAL, MF
    RICHARDSON, EP
    BIRD, ED
    MARTIN, JB
    [J]. SCIENCE, 1985, 230 (4725) : 561 - 563