TY - JOUR
T1 - Hydrogen sulfide is neuroprotective in Alzheimer’s disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation
AU - Giovinazzo, Daniel
AU - Bursac, Biljana
AU - Sbodio, Juan I.
AU - Nalluru, Sumedha
AU - Vignane, Thibaut
AU - Snowman, Adele M.
AU - Albacarys, Lauren M.
AU - Sedlak, Thomas W.
AU - Torregrossa, Roberta
AU - Whiteman, Matthew
AU - Filipovic, Milos R.
AU - Snyder, Solomon H.
AU - Paul, Bindu D.
N1 - Funding Information:
This work was supported by US Public Health Service Grant DA044123 (to S.H.S.); American Heart Association (AHA)–Allen Initiative in Brain Health and Cognitive Impairment (to S.H.S. and associates); Medical Research Council, United Kingdom (MR/S002626/1 to M.W.); the Brian Ridge Scholarship (R.T.); and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (864921 to M.R.F.). We are grateful to Olga Pletnikova, Brain Resource Center at Johns Hopkins University, for providing postmortem AD brain samples. The Johns Hopkins University Mass Spectrometry Core is acknowledged for analysis of protein sulfhydration. We especially thank the reviewers for their valuable comments and suggestions, which have greatly strengthened the study.
Funding Information:
ACKNOWLEDGMENTS. This work was supported by US Public Health Service Grant DA044123 (to S.H.S.); American Heart Association (AHA)–Allen Initiative in Brain Health and Cognitive Impairment (to S.H.S. and associates); Medical Research Council, United Kingdom (MR/S002626/1 to M.W.); the Brian Ridge Scholarship (R.T.); and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (864921 to M.R.F.). We are grateful to Olga Pletnikova, Brain Resource Center at Johns Hopkins University, for providing postmortem AD brain samples. The Johns Hopkins University Mass Spectrometry Core is acknowledged for analysis of protein sulfhydration. We especially thank the reviewers for their valuable comments and suggestions, which have greatly strengthened the study.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/1/26
Y1 - 2021/1/26
N2 - Alzheimer’s disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3β (GSK3β). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.
AB - Alzheimer’s disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3β (GSK3β). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.
KW - Alzheimer’s disease
KW - GSK3beta
KW - Hydrogen sulfide
KW - Sulfhydration
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=85099898330&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099898330&partnerID=8YFLogxK
U2 - 10.1073/pnas.2017225118
DO - 10.1073/pnas.2017225118
M3 - Article
C2 - 33431651
AN - SCOPUS:85099898330
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
M1 - e2017225118
ER -