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.
(Cysteine is also necessary for glutathione synthesis )
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.
(Cysteine is also necessary for glutathione synthesis )
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