Work

Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease

Year: 2016

Type: article

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.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.1608264113

Authors: Juan I. Sbodio, Solomon H. Snyder, Bindu D. Paul

Institutions: Johns Hopkins University, Johns Hopkins Medicine

Language: English

Topic: Genetic Neurodegenerative Diseases

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: CHDI Foundation, National Institute of Mental Health, National Institute on Drug Abuse