α Pix enhances mutant huntingtin aggregation

被引：13

作者：

Eriguchi, Makoto ^{[1
]}

Mizuta, Haruo ^{[1
]}

Luo, Shouqing ^{[2
]}

Kuroda, Yasuo ^{[1
]}

Hara, Hideo ^{[1
]}

Rubinsztein, David C. ^{[2
]}

机构：

[1] Saga Univ, Div Neurol, Fac Med, Dept Internal Med, Saga 8498501, Japan

[2] Addenbrookes Hosp, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 2XY, England

来源：

JOURNAL OF THE NEUROLOGICAL SCIENCES | 2010年 / 290卷 / 1-2期

基金：

英国惠康基金;

关键词：

alpha Pix; Pix; Huntingtin; Polyglutamine; Neurodegenerative disease; Aggregation; NUCLEOTIDE EXCHANGE FACTORS; LINKED MENTAL-RETARDATION; BETA-PIX; CASPASE CLEAVAGE; RHO-GTPASES; TOXICITY; CALPAIN; KINASES; DISEASE; PAK;

D O I：

10.1016/j.jns.2009.11.003

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

Huntington's disease is caused by polyglutamine-expanded mutant huntingtin (muhtt), an aggregation-prone protein. We identified the Pak-interacting exchange factor (alpha Pix/Cool2) as a novel huntingtin (htt) interacting protein, after screening actin-cytoskeleton organization-related factors. Using immunoprecipitation experiments, we show that alpha Pix binds to both the N-terminal of wild-type htt (wthtt) and mutant htt (muthtt). Colocalization studies revealed that (x Pix accumulates in muthtt aggregates. Deletion analysis suggested that the dbl homology (DH) and pleckstrin homology (PH) domains of alpha Pix are required for its interaction with htt. Overexpression of ot Pix enhanced muthtt aggregation by inducing SDS-soluble muthtt-muthtt interactions. Conversely, knocking down ot Pix attenuated muhtt aggregation. These findings suggest that ot Pix plays an important role in muthtt aggregation. (C) 2009 Elsevier B.V. All rights reserved.

引用

页码：80 / 85

页数：6

共 23 条

[1]

PAK3 mutation in nonsyndromic X-linked mental retardation [J].

Allen, KM ;

Gleeson, JG ;

Bagrodia, S ;

Partington, MW ;

MacMillan, JC ;

Cerione, RA ;

Mulley, JC ;

Walsh, CA .

NATURE GENETICS, 1998, 20 (01) :25-30

[2]

Biology of the p21-activated kinases [J].

Bokoch, GM .

ANNUAL REVIEW OF BIOCHEMISTRY, 2003, 72 :743-781

[3]

αPix stimulates p21-activated kinase activity through exchange factor-dependent and -independent mechanisms [J].

Daniels, RH ;

Zenke, FT ;

Bokoch, GM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (10) :6047-6050

[4]

Inhibition of calpain cleavage of huntingtin reduces toxicity - Accumulation of calpain/caspase fragments in the nucleus [J].

Gafni, J ;

Hermel, E ;

Young, JE ;

Wellington, CL ;

Hayden, MR ;

Ellerby, LM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (19) :20211-20220

[5]

Calpain activation in Huntington's disease [J].

Gafni, J ;

Ellerby, LM .

JOURNAL OF NEUROSCIENCE, 2002, 22 (12) :4842-4849

[6]

A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease [J].

Goehler, H ;

Lalowski, M ;

Stelzl, U ;

Waelter, S ;

Stroedicke, M ;

Worm, U ;

Droege, A ;

Lindenberg, KS ;

Knoblich, M ;

Haenig, C ;

Herbst, M ;

Suopanki, J ;

Scherzinger, E ;

Abraham, C ;

Bauer, B ;

Hasenbank, R ;

Fritzsche, A ;

Ludewig, AH ;

Buessow, K ;

Coleman, SH ;

Gutekunst, CA ;

Landwehrmeyer, BG ;

Lehrach, H ;

Wanker, EE .

MOLECULAR CELL, 2004, 15 (06) :853-865

[7]

Kumar Lokesh, 2006, In Silico Biology, V6, P71

[8]

Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation [J].

Kutsche, K ;

Yntema, H ;

Brandt, A ;

Jantke, I ;

Nothwang, HG ;

Orth, U ;

Boavida, MG ;

David, D ;

Chelly, J ;

Fryns, JP ;

Moraine, C ;

Ropers, HH ;

Hamel, BCJ ;

van Bokhoven, H ;

Gal, A .

NATURE GENETICS, 2000, 26 (02) :247-250

[9]

Proteases acting on mutant Huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions [J].

Lunkes, A ;

Lindenberg, KS ;

Ben-Haïem, L ;

Weber, C ;

Devys, D ;

Landwehrmeyer, GB ;

Mandel, JL ;

Trottier, Y .

MOLECULAR CELL, 2002, 10 (02) :259-269

[10]

p21-activated kinase 1 promotes soluble mutant huntingtin self-interaction and enhances toxicity [J].

Luo, Shouqing ;

Mizuta, Haruo ;

Rubinsztein, David C. .

HUMAN MOLECULAR GENETICS, 2008, 17 (06) :895-905

← 1 2 3 →