TY - JOUR
T1 - Golgi protein ACBD3 mediates neurotoxicity associated with huntington's disease
AU - Sbodio, Juan
AU - Paul, Bindu D.
AU - Machamer, Carolyn E.
AU - Snyder, Solomon H.
N1 - Funding Information:
We thank Juan Troncoso and Olga Pletnikova for the postmortem human patient striatal samples. This work was supported by grants to S.H.S. from the U.S. Public Health Service (MH18501) and the Cure Huntington’s Disease Initiative and by National Institutes of Health grant R01 GM42522 to C.E.M.
PY - 2013/5/12
Y1 - 2013/5/12
N2 - Huntington@s disease (HD) is an autosomal-dominant neurodegenerative disease caused by the expansion of polyglutamine repeats in the gene for huntingtin (. Htt). In HD, the corpus striatum selectively degenerates despite the uniform expression of mutant huntingtin (mHtt) throughout the brain and body. Striatal selectivity reflects the binding of the striatal-selective protein Rhes to mHtt to augment cytotoxicity, but molecular mechanisms underlying the toxicity have been elusive. Here, we report that the Golgi protein acyl-CoA binding domain containing 3 (ACBD3) mediates mHtt cytotoxicity via a Rhes/mHtt/ACBD3 complex. ACBD3 levels are markedly elevated in the striatum of HD patients, in a striatal cell line harboring polyglutamine repeats, and in the brains of HD mice. Moreover, ACBD3 deletion abolishes HD neurotoxicity, which is increased by ACBD3 overexpression. Enhanced levels of ACBD3 elicited by endoplasmic reticulum, mitochondrial, and Golgi stresses may account for HD-associated augmentation of ACBD3 and neurodegeneration
AB - Huntington@s disease (HD) is an autosomal-dominant neurodegenerative disease caused by the expansion of polyglutamine repeats in the gene for huntingtin (. Htt). In HD, the corpus striatum selectively degenerates despite the uniform expression of mutant huntingtin (mHtt) throughout the brain and body. Striatal selectivity reflects the binding of the striatal-selective protein Rhes to mHtt to augment cytotoxicity, but molecular mechanisms underlying the toxicity have been elusive. Here, we report that the Golgi protein acyl-CoA binding domain containing 3 (ACBD3) mediates mHtt cytotoxicity via a Rhes/mHtt/ACBD3 complex. ACBD3 levels are markedly elevated in the striatum of HD patients, in a striatal cell line harboring polyglutamine repeats, and in the brains of HD mice. Moreover, ACBD3 deletion abolishes HD neurotoxicity, which is increased by ACBD3 overexpression. Enhanced levels of ACBD3 elicited by endoplasmic reticulum, mitochondrial, and Golgi stresses may account for HD-associated augmentation of ACBD3 and neurodegeneration
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U2 - 10.1016/j.celrep.2013.08.001
DO - 10.1016/j.celrep.2013.08.001
M3 - Article
C2 - 24012756
AN - SCOPUS:84884138290
VL - 4
SP - 890
EP - 897
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 5
ER -