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Dysregulated hydrogen sulfide metabolism links aberrant neuronal stress responses and neurodegeneration in Huntington's disease
Author(s) -
Paul Bindu Diana,
Snyder Solomon H.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02150
Subject(s) - neurodegeneration , cystathionine beta synthase , oxidative stress , hypotaurine , chemistry , cysteine , huntingtin , microbiology and biotechnology , biochemistry , cystathionine gamma lyase , transsulfuration , biology , amino acid , enzyme , medicine , disease , gene , mutant , taurine
Hydrogen sulfide (H 2 S) is a gaseous signaling molecule that plays central roles in a myriad of physiological processes ranging from response to oxidative stress and transcriptional regulation. Hydrogen sulfide is synthesized endogenously from the semi‐essential amino acid cysteine via the reverse transsulfuration pathway. Thus disrupted cysteine metabolism may also lead to aberrant H 2 S signaling. One of the modes by which hydrogen sulfide signals is by a posttranslational modification designated as sulfhydration/persulfidation, which occurs on reactive cysteine residues on target proteins, where the reactive SH group is converted to an SSH group. Sulfhydration is a highly prevalent modification which modifies the structure and/or activity of target proteins. Research on H 2 S and persulfidation is still in its infancy. We show here that H 2 S is generated in response to stress stimuli such as Golgi stress and oxidative stress in neurons, which modulates sulfhydration levels to modulate signaling pathways. We further show that these cytoprotective stress responses are compromised in striatal cell culture model and the R6/2 and Q175 mouse models of Huntington’s disease (HD). We have shown previously that the biosynthetic enzyme for cysteine and H 2 S in neurons, cystathionine g‐lyase (CSE) is depleted in HD and mediates neurodegeneraton. HD is a neurodegenerative disease which is triggered by expansion of polyglutamine repeats in the protein huntingtin, which causes it to aggregate and elicit multi‐system toxicity. Restoring H 2 S balance in cells mitigates neuronal dysfunction in neurodegenerative diseases such as HD. A screen for regulators of the transsulfuration pathway has resulted in identification of compounds that modulate cysteine balance and disease progression in HD. Support or Funding Information United States Public Health Service (USPHS) grants DA000266 and MH18501 to S.H.S.References 1 Paul BD , Sbodio JI , Xu R , Vandiver MS , Cha JY , Snowman AM and Snyder SH. Cystathionine g-lyase deficiency mediates neurodegeneration in Huntington’s disease . Nature 2014 ; 509 ( 7498 ) 96 – 1002 Sbodio JI # , Snyder SH * and Paul BD # * . Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington’s disease . Proc Natl Acad Sci USA . 2018 ; 115 ( 4 ): 780 – 785 .( # Equal contribution,* Co-corresponding author ). 3 Sbodio JI , Snyder SH * and Paul BD * Redox mechanisms in neurodegeneration: From disease outcomes to therapeutic opportunities . Antioxid Redox Signal . 2019 ; 30 ( 11 ): 1450 – 1499 (* Co-corresponding author ).