Disruption of axonal transport by loss of huntingtin or expression of pathogenic PolyQ proteins in Drosophila

被引:499
作者
Gunawardena, S
Her, LS
Brusch, RG
Laymon, RA
Niesman, IR
Gordesky-Gold, B
Sintasath, L
Bonini, NM
Goldstein, LSB [1 ]
机构
[1] Univ Calif San Diego, Dept Cellular & Mol Physiol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA
[3] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA
关键词
D O I
10.1016/S0896-6273(03)00594-4
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
We tested whether proteins implicated in Huntington's and other polyglutamine (polyQ) expansion diseases can cause axonal transport defects. Reduction of Drosophila huntingtin and expression of proteins containing pathogenic polyQ repeats disrupt axonal transport. Pathogenic polyQ proteins accumulate in axonal and nuclear inclusions, titrate soluble motor proteins, and cause neuronal apoptosis and organismal death. Expression of a cytoplasmic polyQ repeat protein causes adult retinal degeneration, axonal blockages in larval neurons, and larval lethality, but not neuronal apoptosis or nuclear inclusions. A nuclear polyQ repeat protein induces neuronal apoptosis and larval lethality but no axonal blockages. We suggest that pathogenic polyQ proteins cause neuronal dysfunction and organismal death by two non-mutually exclusive mechanisms. One mechanism requires nuclear accumulation and induces apoptosis; the other interferes with axonal transport. Thus, disruption of axonal transport by pathogenic polyQ proteins could contribute to early neuropathology in Huntington's and other polyQ expansion diseases.
引用
收藏
页码:25 / 40
页数:16
相关论文
共 50 条
[1]   Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease [J].
Auluck, PK ;
Chan, HYE ;
Trojanowski, JQ ;
Lee, VMY ;
Bonini, NM .
SCIENCE, 2002, 295 (5556) :865-868
[2]   Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: Correlation between the density of inclusions and IT15 CAG triplet repeat length [J].
Becher, MW ;
Kotzuk, JA ;
Sharp, AH ;
Davies, SW ;
Bates, GP ;
Price, DL ;
Ross, CA .
NEUROBIOLOGY OF DISEASE, 1998, 4 (06) :387-397
[3]   Regulating axon branch stability: The role of p190 RhoGAP in repressing a retraction signaling pathway [J].
Billuart, P ;
Winter, CG ;
Maresh, A ;
Zhao, XS ;
Luo, LQ .
CELL, 2001, 107 (02) :195-207
[4]   Fast transport and retrograde movement of huntingtin and HAP 1 in axons [J].
BlockGalarza, J ;
Chase, KO ;
Sapp, E ;
Vaughn, KT ;
Vallee, RB ;
DiFiglia, M ;
Aronin, N .
NEUROREPORT, 1997, 8 (9-10) :2247-2251
[5]   Chaperoning brain degeneration [J].
Bonini, NM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 :16407-16411
[6]   Kinesin-dependent axonal transport is mediated by the Sunday driver (SYD) protein [J].
Bowman, AB ;
Kamal, A ;
Ritchings, BW ;
Philp, AV ;
McGrail, M ;
Gindhart, JG ;
Goldstein, LSB .
CELL, 2000, 103 (04) :583-594
[7]  
Bowman AB, 1999, J CELL BIOL, V146, P165
[8]   A molecular genetic analysis of the interaction between the cytoplasmic dynein intermediate chain and the Glued (dynactin) complex [J].
Boylan, K ;
Serr, M ;
Hays, T .
MOLECULAR BIOLOGY OF THE CELL, 2000, 11 (11) :3791-3803
[9]   Loss of normal huntingtin function: new developments in Huntington's disease research [J].
Cattaneo, E ;
Rigamonti, D ;
Goffredo, D ;
Zuccato, C ;
Squitieri, F ;
Sipione, S .
TRENDS IN NEUROSCIENCES, 2001, 24 (03) :182-188
[10]   Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain [J].
DiFiglia, M ;
Sapp, E ;
Chase, KO ;
Davies, SW ;
Bates, GP ;
Vonsattel, JP ;
Aronin, N .
SCIENCE, 1997, 277 (5334) :1990-1993