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


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.

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Figure 1: CSE is expressed in the brain and is depleted in Huntington’s disease.
Figure 2: Decreased CSE activity and growth in striatal Q111 cells.
Figure 3: CSE is depleted at the transcriptional level in Huntington’s disease.
Figure 4: CSE protects against oxidative stress, and cysteine supplementation delays neurodegeneration.


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We thank J. C. Troncoso and O. Pletnikova for providing the human post-mortem tissue samples; D. Krainc for the constructs CMV-SP1 and TAF4; M. MacDonald for the striatal Q7 and Q111 cell lines; and the Cure Huntington’s Disease Initiative (CHDI) for the Q175 mice tissues. This work was supported by United States Public Health Service Grant MH18501 to S.H.S. and by the CHDI. M.S.V. and R.X. are supported by the National Institutes of Health Medical Scientist Training Program Award.

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B.D.P. and S.H.S. designed the research. B.D.P., J.S., R.X., M.S.V. and J.C. conducted experiments. B.D.P., J.S. and R.X. analysed data. A.M.S. prepared plasmid constructs and provided technical assistance. B.D.P. and S.H.S. wrote the paper.

Corresponding author

Correspondence to Solomon H. Snyder.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 CSE expression is not altered in the brain in amyotrophic lateral sclerosis, multiple sclerosis and spinocerebellar ataxia.

a, Western blots show that CSE expression in the motor cortex of samples from controls and patients with amyotrophic lateral sclerosis (ALS) showing substantial neurodegeneration in the motor cortex are similar. Extracts were prepared from the motor cortex and analysed for CSE expression using anti-CSE antibodies and β-actin as a loading control. b, Expression of CSE is not altered in the corpus callosum of patients with multiple sclerosis (MS), where multiple lesions, demyelination and decrease in oligodendrocytes was observed in the corpus callosum of the brain. c, d, Levels of CSE do not change in the cerebral cortex (c) or cerebellum (d) of patients with spinocerebellar ataxia (SCA). Neuropathological analysis of the brains of these patients revealed severe neuronal loss and gliosis in the cerebellum.

Extended Data Figure 2 Cse−/− mice are more vulnerable to stress induced by 3-nitropropionic acid.

Wild-type and Cse−/− male mice at 8 months of age were injected with a single dose of 3-nitropropionic acid (3-NP) (100 mg kg−1), and lysates were prepared 24 h later from the striatum and cortex and analysed for oxidative stress. a, b, Striata (a) and cortex (b) of Cse−/− mice show elevated protein oxidation as measured by protein carbonylation, which is more pronounced in the striatum. n = 3 (means ± s.e.m.). c, d, Cse−/− mice also show augmented levels of protein nitration in the striatum (c) and cortex (d) in comparison with wild-type mice. Note the increased basal level of protein oxidation in the Cse−/− mice.

Supplementary information

Clasping test with a wild type mouse on a control diet

An 11-week old wild type mouse exhibiting a normal righting response when suspended by the tail. The mouse was placed on a control diet containing 0.3% cystine and regular drinking water. (MOV 7054 kb)

Clasping test with an R6/2 transgenic mouse on a control diet

An 11-week old R6/2 transgenic wild type mouse with motor deficits clasping its hind limbs almost immediately when suspended by the tail. The R6/2 mouse was placed on a control diet containing 0.3% cystine and regular drinking water. (MOV 6740 kb)

Clasping test with an R6/2 transgenic mouse on N-acetyl cysteine and a high cysteine diet

An 11-week old R6/2 transgenic mouse showing almost no clasping when suspended by the tail. The R6/2 mouse was placed on a diet containing 0.8% cystine and 20 mM N-acetylcysteine in the drinking water. (MOV 6394 kb)

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Paul, B., Sbodio, J., Xu, R. et al. Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington’s disease. Nature 509, 96–100 (2014).

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