Journal Article

Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington’s disease

Vandiver, M. Scott, Cha, Jiyoung Y., Sbodio, Juan I., Snyder, Solomon H., Xu, Risheng, Paul, Bindu D., Snowman, Adele M.

2014

Overview

Cystathionine γ-lyase, which is responsible for the production of cysteine, is decreased in the striatum and cortex of mouse models of Huntington’s disease and in patients with Huntington’s disease, and cysteine supplementation in diet and drinking water partly rescues the phenotype and the diminished longevity of the mouse model. Cysteine link in Huntington's disease Huntington's disease is associated with polyglutamine expansion in the gene encoding huntingtin. Mutant huntingtin is expressed throughout the brain and rest of the body, but the striatum is the most affected brain region. Here it is shown that the enzyme cystathionine γ-lyase (CSE), responsible for cysteine biosynthesis, is decreased in the striatum and cortex of both mouse models and Huntington's disease patients. Mutant huntingtin inhibits the transcriptional activator Sp1, resulting in decreased CSE transcription. Cysteine supplementation in diet and drinking water partially rescues the phenotype and the diminished longevity in the mouse model, suggesting that cysteine supplementation might be beneficial for Huntington's disease patients. Huntington’s disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes 1 . Huntington’s disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington’s disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity 2 . Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington’s disease tissues, which may mediate Huntington’s disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington’s disease tissues and in intact mouse models of Huntington’s disease, suggesting therapeutic potential.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1689/1558 / Animals / Brain - enzymology / Corpus Striatum - drug effects / Corpus Striatum - enzymology / Corpus Striatum - metabolism / Corpus Striatum - pathology / Cystathionine gamma-Lyase - deficiency / Cystathionine gamma-Lyase - genetics / Cysteine - administration & dosage / Cysteine - biosynthesis / Cysteine - pharmacology / Cysteine - therapeutic use / Cysteine proteinases / Development and progression / Dietary Supplements / Disease Models, Animal / Drinking Water - chemistry / Gene Deletion / Gene Expression Regulation, Enzymologic - genetics / Humanities and Social Sciences / Huntingtin Protein / Huntington Disease - drug therapy / Huntington Disease - enzymology / Huntington Disease - genetics / Huntington Disease - pathology / Huntington's chorea / letter / Male / Mice / multidisciplinary / Mutant Proteins - genetics / Mutant Proteins - metabolism / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neuroprotective Agents - administration & dosage / Neuroprotective Agents - metabolism / Neuroprotective Agents - pharmacology / Neuroprotective Agents - therapeutic use / Oxidative Stress - drug effects / Physiological aspects / Risk factors / Science / Sp1 Transcription Factor - antagonists & inhibitors / Sp1 Transcription Factor - metabolism / Transcription, Genetic - genetics