title: Golgi protein ACBD3 mediates neurotoxicity associated with Huntington's disease.
abstract: 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.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Sbodio
authors.forename: Bindu D
authors.initials: BD
authors.lastname: Paul
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Machamer
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000821:virology; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
chemical_list: C449459:ACBD3 protein, human; D048868:Adaptor Proteins, Signal Transducing; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D019204:GTP-Binding Proteins; C486702:RASD2 protein, human