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Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington's disease.
- Source :
-
Nature [Nature] 2014 May 01; Vol. 509 (7498), pp. 96-100. Date of Electronic Publication: 2014 Mar 26. - Publication Year :
- 2014
-
Abstract
- 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. 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. 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.
- Subjects :
- Animals
Brain enzymology
Corpus Striatum drug effects
Corpus Striatum enzymology
Corpus Striatum metabolism
Corpus Striatum pathology
Cystathionine gamma-Lyase genetics
Cysteine administration & dosage
Cysteine biosynthesis
Cysteine pharmacology
Cysteine therapeutic use
Dietary Supplements
Disease Models, Animal
Drinking Water chemistry
Gene Deletion
Gene Expression Regulation, Enzymologic genetics
Huntingtin Protein
Huntington Disease drug therapy
Huntington Disease genetics
Male
Mice
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
Sp1 Transcription Factor antagonists & inhibitors
Sp1 Transcription Factor metabolism
Transcription, Genetic genetics
Cystathionine gamma-Lyase deficiency
Huntington Disease enzymology
Huntington Disease pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 509
- Issue :
- 7498
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 24670645
- Full Text :
- https://doi.org/10.1038/nature13136