alpha Pix enhances mutant huntingtin aggregation.
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 alpha 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 alpha Pix enhanced muthtt aggregation by inducing SDS-soluble muthtt-muthtt interactions. Conversely, knocking down alpha Pix attenuated muhtt aggregation. These findings suggest that alpha Pix plays an important role in muthtt aggregation.
Eriguchi
Makoto
M
Department of Internal Medicine, Saga University Faculty of Medicine, Saga 849-8501, Japan.
Mizuta
Haruo
H
Luo
Shouqing
S
Kuroda
Yasuo
Y
Hara
Hideo
H
Rubinsztein
David C
DC
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D034622:RNA Interference; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
C576603:ARHGEF6 protein, human; D003598:Cytoskeletal Proteins; D020662:Guanine Nucleotide Exchange Factors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D064067:Rho Guanine Nucleotide Exchange Factors; C097188:polyglutamine