title: Transcriptional control of amino acid homeostasis is disrupted in Huntington's disease.
abstract: Disturbances in amino acid metabolism, which have been observed in Huntington's disease (HD), may account for the profound inanition of HD patients. HD is triggered by an expansion of polyglutamine repeats in the protein huntingtin (Htt), impacting diverse cellular processes, ranging from transcriptional regulation to cognitive and motor functions. We show here that the master regulator of amino acid homeostasis, activating transcription factor 4 (ATF4), is dysfunctional in HD because of oxidative stress contributed by aberrant cysteine biosynthesis and transport. Consistent with these observations, antioxidant supplementation reverses the disordered ATF4 response to nutrient stress. Our findings establish a molecular link between amino acid disposition and oxidative stress leading to cytotoxicity. This signaling cascade may be relevant to other diseases involving redox imbalance and deficits in amino acid metabolism.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Juan I
authors.initials: JI
authors.lastname: Sbodio
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 ssnyder@jhmi.edu bpaul8@jhmi.edu.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; ssnyder@jhmi.edu bpaul8@jhmi.edu.
authors.forename: Bindu D
authors.initials: BD
authors.lastname: Paul
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003542:Cystathionine gamma-Lyase / Q000172:deficiency / Q000235:genetics; D003545:Cysteine / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D018384:Oxidative Stress
chemical_list: C497109:ATF4 protein, human; D000596:Amino Acids; D051701:Activating Transcription Factor 4; D003542:Cystathionine gamma-Lyase; D003545:Cysteine
keywords: ATF4; CSE; Huntington’s disease; cysteine; oxidative stress