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

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 changes1. 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 neurotoxicity2. 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.

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

“…We also reported a marked depletion of cystathionine γ-lyase (CSE) in HD (51). CSE is a rate-limiting enzyme in the biosynthesis of cysteine and generation of the gasotransmitter hydrogen sulfide (51,52). Treating R6/2 mice with cysteine or cysteine precursors markedly improves the motor performance of R6/2 mice, similar to the improvement that we have observed with viral delivery of IPMK.…”

“…4J) (50). We also reported a marked depletion of cystathionine γ-lyase (CSE) in HD (51). CSE is a rate-limiting enzyme in the biosynthesis of cysteine and generation of the gasotransmitter hydrogen sulfide (51,52).…”

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

“…H 2 S also confers cytoprotection via suppression of inflammation (17) and by protecting mitochondrial function and integrity (17,18). Decreased levels of H 2 S in brain tissue are associated with neurodegenerative age-related diseases such as Parkinson's (19), and administration of H 2 S has been shown protective in experimental models for this disease (20)(21)(22). Decreased levels of CSE have recently been observed in human Huntington disease tissues and in a mouse Huntington model (22).…”

“…Decreased levels of H 2 S in brain tissue are associated with neurodegenerative age-related diseases such as Parkinson's (19), and administration of H 2 S has been shown protective in experimental models for this disease (20)(21)(22). Decreased levels of CSE have recently been observed in human Huntington disease tissues and in a mouse Huntington model (22). After addition of sodium hydrogen sulfide and L-cysteine, levels of protein persulfidation (also called protein S-sulfhydration) increased in a CSE-dependent manner in vitro (23), suggesting an influential effect of this type of posttranslational protein modification.…”

Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

“…Recently, several studies have implicated the accumulation of this product, as well as decreases in cysteine, which are also observed in Gpt2-null brains, in neurodegenerative disease. More specifically, through deficiency in cystathionine γ-lyase and mechanisms involving both redox homeostasis and sulfhydration, this metabolic pathway has been pinpointed in both Huntington's disease (36,37) and Parkinson's disease (38), as well as other neurological diseases with mitochondrial defects. Other statistically significant perturbations in P18 brain supporting abnormalities in neuroprotective mechanisms include reductions in glutathione and folate.…”