Effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability

Elena A. Ostrakhovitch; Eun Suk Song; Johannah E. Stegemann; Michael McLeod; Tritia R. Yamasaki

doi:10.1038/s41598-025-99794-z

Effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability

Elena A. Ostrakhovitch
, Eun Suk Song
, Johannah E. Stegemann
, Michael McLeod
, Tritia R. Yamasaki

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterized by nigrostriatal degeneration and aggregation of α-synuclein (α-Syn) with accumulation of insoluble aggregates in Lewy bodies. Familial mutations in α-Syn are associated with the development of PD. Accumulation of insoluble aggregates results in neuronal toxicity. Identification of compounds that inhibit seeding activity of α-Syn is of great importance. Here we investigate the potential of H2S donor, sodium hydrosulfide (NaHS), to inhibit α-Syn aggregation. We examined the effect of NaHS on fibril growth kinetics and the structural change of α-Syn fibrils formed by self-seeding and cross-seeding of wild-type (wt) and PD familial α-Syn mutations. NaHS slowed both self- and cross-seeded A53T α-Syn fibril formation but not wild-type fibril formation. We observed a decrease in the formed fibril length in vitro. We examined the effect on fibril formation within cells. NaHS significantly reduced the number and filament length of formed oligomers in an α-Syn overexpressing cell model. Furthermore, NaHS rescued viability of A53T α-Syn overexpressing cells seeded with wt- and mutant preformed fibrils. These results support a conformation-specific effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability which deserves further exploration for therapeutic potential.

Original language	English
Article number	15597
Journal	Scientific Reports
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41598-025-99794-z
State	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025.

Funding

This work was supported by a VA Career Development Award # IK2 BX 008443 from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service (TRY) and University of Kentucky CNS Metabolism (CNS-Met) COBRE, supported by a grant from the National Institute of General Medical Sciences NIGMS (P20 GM148326) from the National Institutes of Health (TRY). Electron microscopy experiments were supported by KY INBRE Core Utilization Voucher Program (KBRIN) (TRY) under a grant from the National Institutes of Health National Institute of General Medical Sciences (5P20GM103436-24).

Funders	Funder number
TRY
University of Kentucky CNS Metabolism
National Institutes of Health (NIH)
INBRE Core Utilization Voucher Program
KBRIN
US Department of Veterans Affairs Biomedical Laboratory Research and Development Service
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	P20 GM148326, 5P20GM103436-24

Keywords

Hydrogen sulfide
Parkinson disease
Protein aggregation
α-Synuclein

ASJC Scopus subject areas

General

Access to Document

10.1038/s41598-025-99794-z

Cite this

@article{e49646585f3540c7abbdc740bffe2b52,

title = "Effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability",

abstract = "Parkinson{\textquoteright}s disease (PD) is a progressive neurodegenerative movement disorder characterized by nigrostriatal degeneration and aggregation of α-synuclein (α-Syn) with accumulation of insoluble aggregates in Lewy bodies. Familial mutations in α-Syn are associated with the development of PD. Accumulation of insoluble aggregates results in neuronal toxicity. Identification of compounds that inhibit seeding activity of α-Syn is of great importance. Here we investigate the potential of H2S donor, sodium hydrosulfide (NaHS), to inhibit α-Syn aggregation. We examined the effect of NaHS on fibril growth kinetics and the structural change of α-Syn fibrils formed by self-seeding and cross-seeding of wild-type (wt) and PD familial α-Syn mutations. NaHS slowed both self- and cross-seeded A53T α-Syn fibril formation but not wild-type fibril formation. We observed a decrease in the formed fibril length in vitro. We examined the effect on fibril formation within cells. NaHS significantly reduced the number and filament length of formed oligomers in an α-Syn overexpressing cell model. Furthermore, NaHS rescued viability of A53T α-Syn overexpressing cells seeded with wt- and mutant preformed fibrils. These results support a conformation-specific effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability which deserves further exploration for therapeutic potential.",

keywords = "Hydrogen sulfide, Parkinson disease, Protein aggregation, α-Synuclein",

author = "Ostrakhovitch, \{Elena A.\} and Song, \{Eun Suk\} and Stegemann, \{Johannah E.\} and Michael McLeod and Yamasaki, \{Tritia R.\}",

note = "Publisher Copyright: {\textcopyright} This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025.",

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doi = "10.1038/s41598-025-99794-z",

language = "English",

volume = "15",

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AU - Ostrakhovitch, Elena A.

AU - Song, Eun Suk

AU - Stegemann, Johannah E.

AU - McLeod, Michael

AU - Yamasaki, Tritia R.

N1 - Publisher Copyright: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025.

PY - 2025/12

Y1 - 2025/12

N2 - Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterized by nigrostriatal degeneration and aggregation of α-synuclein (α-Syn) with accumulation of insoluble aggregates in Lewy bodies. Familial mutations in α-Syn are associated with the development of PD. Accumulation of insoluble aggregates results in neuronal toxicity. Identification of compounds that inhibit seeding activity of α-Syn is of great importance. Here we investigate the potential of H2S donor, sodium hydrosulfide (NaHS), to inhibit α-Syn aggregation. We examined the effect of NaHS on fibril growth kinetics and the structural change of α-Syn fibrils formed by self-seeding and cross-seeding of wild-type (wt) and PD familial α-Syn mutations. NaHS slowed both self- and cross-seeded A53T α-Syn fibril formation but not wild-type fibril formation. We observed a decrease in the formed fibril length in vitro. We examined the effect on fibril formation within cells. NaHS significantly reduced the number and filament length of formed oligomers in an α-Syn overexpressing cell model. Furthermore, NaHS rescued viability of A53T α-Syn overexpressing cells seeded with wt- and mutant preformed fibrils. These results support a conformation-specific effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability which deserves further exploration for therapeutic potential.

AB - Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterized by nigrostriatal degeneration and aggregation of α-synuclein (α-Syn) with accumulation of insoluble aggregates in Lewy bodies. Familial mutations in α-Syn are associated with the development of PD. Accumulation of insoluble aggregates results in neuronal toxicity. Identification of compounds that inhibit seeding activity of α-Syn is of great importance. Here we investigate the potential of H2S donor, sodium hydrosulfide (NaHS), to inhibit α-Syn aggregation. We examined the effect of NaHS on fibril growth kinetics and the structural change of α-Syn fibrils formed by self-seeding and cross-seeding of wild-type (wt) and PD familial α-Syn mutations. NaHS slowed both self- and cross-seeded A53T α-Syn fibril formation but not wild-type fibril formation. We observed a decrease in the formed fibril length in vitro. We examined the effect on fibril formation within cells. NaHS significantly reduced the number and filament length of formed oligomers in an α-Syn overexpressing cell model. Furthermore, NaHS rescued viability of A53T α-Syn overexpressing cells seeded with wt- and mutant preformed fibrils. These results support a conformation-specific effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability which deserves further exploration for therapeutic potential.

KW - Hydrogen sulfide

KW - Parkinson disease

KW - Protein aggregation

KW - α-Synuclein

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JO - Scientific Reports

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Effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability

Abstract

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Effect of hydrogen sulfide on alpha-synuclein aggregation and cell viability

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