Role of neuronal signaling effector hydrogen sulfide (H2S) and sulfhydration in Huntington's disease

Abstract

Hydrogen sulfide (H2S) has joined the ranks of the gasotransmitters, nitric oxide and carbon monoxide as a signaling molecule that modulates a wide spectrum of physiological processes. H2S signals via sulfhydration, wherein it mediates the conversion of −SH groups of reactive cysteine residues on target proteins to −SSH or persulfide groups. H2S is synthesized by cystathionine gamma lyase (CSE), cystathionine beta synthase (CBS) and 3‐mercaptopyruvate sulfurtransferase of the reverse transsulfuration pathway. Aberrant H2S metabolism is involved in the progressive neurodegeneration seen in Huntington's disease (HD). HD is a devastating condition and is currently considered to be an incurable disease of the nervous system. New treatment options are highly sought after. We asked how normal healthy neural development is influenced by the differential interplay of huntingtin versus mutant huntingtin (mHtt) function vis‐à‐vis CSE and CBS action in the nervous system. Specifically, we sought to understand how the modalities of mutant transformation of huntingtin at the genetic and epigenetic levels affect mHtt effects on H2S action. We chose cell culture and mouse models of HD to study their manifestation on the progressive neurodegeneration observed alongside the cognitive and motor deficits that are characteristic of human HD patients. We have shown that loss of CSE mediates neurodegeneration and disease progression in HD. It appears that the neuronal redox effector functions of H2S are differentially modulated by the action of mHtt on CSE and CBS thereby affecting disease progression in HD by variable regulatory mechanisms.Representative Recognition/HonorASBMB/jbc Herbert Tabor Young Investigator Award (May 2015) at the third European Conference on the Biology of Hydrogen Sulfide at Athens, Greece.Support or Funding InformationUnited States Public Health Service Grant MH18501 to S.H.S, CHDI Foundation