Hydrogen Sulfide Signaling Pathway in Neurodegeneration

Hydrogen Sulfide Signaling Pathway in Neurodegeneration

Overview

Hydrogen sulfide (H₂S) is a gaseous signaling molecule that serves as an important neuromodulator in the brain. Alongside nitric oxide (NO) and carbon monoxide (CO), H₂S belongs to the family of gasotransmitters that regulate neuronal function, synaptic plasticity, and cellular stress responses. In the brain, H₂S is produced endogenously by three main enzymes—cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST)—and plays crucial roles in neuroprotection, anti-oxidation, anti-inflammation, and mitochondrial function [1](https://pubmed.ncbi.nlm.nih.gov/34758326/). [@hydrogen2021]

The biological significance of H₂S in the nervous system has become increasingly apparent over the past two decades. Unlike its reputation as a toxic gas, H₂S at physiological concentrations (nanomolar to low micromolar) serves as a critical signaling molecule with diverse effects on neuronal survival, synaptic transmission, and cellular homeostasis. The dysregulation of H₂S signaling has been implicated in the pathogenesis of multiple neurodegenerative disorders, including [Alzheimer's disease](/diseases/alzheimers-disease) (AD), [Parkinson's disease](/diseases/parkinsons-disease) (PD), [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) (ALS), and [Huntington's disease](/diseases/huntingtons) (HD) [1](https://pubmed.ncbi.nlm.nih.gov/34758326/).

H₂S Biology

Endogenous Production Pathways

Hydrogen Sulfide Signaling Pathway in Neurodegeneration

Overview

Hydrogen sulfide (H₂S) is a gaseous signaling molecule that serves as an important neuromodulator in the brain. Alongside nitric oxide (NO) and carbon monoxide (CO), H₂S belongs to the family of gasotransmitters that regulate neuronal function, synaptic plasticity, and cellular stress responses. In the brain, H₂S is produced endogenously by three main enzymes—cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST)—and plays crucial roles in neuroprotection, anti-oxidation, anti-inflammation, and mitochondrial function [1](https://pubmed.ncbi.nlm.nih.gov/34758326/). [@hydrogen2021]

The biological significance of H₂S in the nervous system has become increasingly apparent over the past two decades. Unlike its reputation as a toxic gas, H₂S at physiological concentrations (nanomolar to low micromolar) serves as a critical signaling molecule with diverse effects on neuronal survival, synaptic transmission, and cellular homeostasis. The dysregulation of H₂S signaling has been implicated in the pathogenesis of multiple neurodegenerative disorders, including [Alzheimer's disease](/diseases/alzheimers-disease) (AD), [Parkinson's disease](/diseases/parkinsons-disease) (PD), [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) (ALS), and [Huntington's disease](/diseases/huntingtons) (HD) [1](https://pubmed.ncbi.nlm.nih.gov/34758326/).

H₂S Biology

Endogenous Production Pathways

The brain produces H₂S through three distinct enzymatic pathways, each with unique cellular distribution and physiological functions:

| Enzyme | Gene | Cellular Location | Substrate | Primary Role | [@mst2022]
|--------|------|-------------------|-----------|--------------| [@h2s_mitochondria2023]
| CBS | CBS | [Neurons](/cell-types/neurons), [astrocytes](/cell-types/astrocytes) | L-cysteine | Major CNS H₂S production | [@cbs2019]
| CSE | CTH | [Endothelial cells](/cell-types/endothelial-cells), peripheral tissues | L-cysteine | Peripheral H₂S production, vascular signaling | [@pd_cse2021]
| 3-MST | MPST | Brain [mitochondria](/organelles/mitochondria), neurons | 3-mercaptopyruvate | Mitochondrial H₂S, redox regulation | [@mst2022]

The three enzymes exhibit distinct subcellular localization: CBS is primarily cytosolic, CSE is partly membrane-associated, and 3-MST localizes to mitochondria where it participates in cellular energy metabolism and redox homeostasis [2](https://pubmed.ncbi.nlm.nih.gov/35678912/). This differential distribution allows for spatially regulated H₂S production in different cellular compartments.

Enzymatic Regulation

CBS Regulation:

• Allosteric activation by S-adenosylmethionine (SAM)
• pH-dependent activity (optimal at physiological pH 7.4)
• Post-translational modifications including phosphorylation
• Transcriptional regulation by oxidative stress

• Constitutive expression in peripheral tissues
• Inducible under hypoxic conditions
• Regulated by glucocorticoids and growth factors

• Partnered with cysteine aminotransferase (CAT)
• Sensitive to mitochondrial redox state
• Activity modulated by glutathione levels

H₂S Sources in Brain

Cellular Signaling Mechanisms

H₂S exerts its biological effects through multiple signaling pathways:

• ATP-sensitive potassium (K_ATP) channels: H₂S induces channel opening, hyperpolarizing neurons
• TRPA1 channels: Ca²⁺ influx and neuronal activation
• Voltage-gated calcium channels: modulation of calcium homeostasis

• NMDA receptor modulation: bidirectional regulation of glutamatergic signaling
• GABA_A receptor effects: interplay with inhibitory neurotransmission

• PI3K/Akt pathway: pro-survival signaling
• ERK1/2 MAPK pathway: cell proliferation and differentiation
• p38 MAPK pathway: stress response modulation

• Nrf2 nuclear translocation: antioxidant response gene activation [3](https://pubmed.ncbi.nlm.nih.gov/33876543/)
• NF-κB inhibition: anti-inflammatory effects
• HIF-1α stabilization: adaptive response to hypoxia

H₂S in Neurodegeneration

Alzheimer's Disease

Alzheimer's disease presents a complex relationship with H₂S signaling, characterized by compensatory changes in H₂S production machinery and altered H₂S homeostasis.

CBS Dysregulation in AD:
CBS activity is significantly elevated in AD brain tissue, particularly in the hippocampus and frontal cortex, representing a compensatory neuroprotective response to accumulating [oxidative stress](/mechanisms/oxidative-stress) and [beta-amyloid](/proteins/amyloid-beta) pathology [4](https://pubmed.ncbi.nlm.nih.gov/32977345/). This upregulation appears to be driven by increased oxidative stress and inflammatory cytokines, which stimulate CBS expression as a endogenous protective mechanism [5](https://pubmed.ncbi.nlm.nih.gov/36543210/). Paradoxically, while CBS activity increases, overall H₂S levels are decreased in AD patients, suggesting either increased consumption or impaired release of H₂S at synaptic terminals.

Amyloid Pathology:
H₂S reduces [amyloid-beta](/proteins/amyloid-beta) production through multiple mechanisms:

• Direct modulation of [γ-secretase](/entities/gamma-secretase) activity
• Inhibition of β-site amyloid precursor protein cleaving enzyme (BACE1)
• Enhanced clearance via [autophagy](/mechanisms/autophagy-lysosome-pathway) pathways [6](https://pubmed.ncbi.nlm.nih.gov/35123456/)

• Protein phosphatase 2A (PP2A) activation
• GSK-3β inhibition
• Reduction of oxidative stress-mediated tau oxidation

• Preservation of long-term potentiation (LTP)
• Upregulation of synaptic proteins (synapsin, PSD-95)
• Protection against amyloid-induced synaptic toxicity
• Enhancement of dendritic spine density

• Heme oxygenase-1 (HO-1)
• Superoxide dismutase (SOD)
• Glutathione peroxidase
• Catalase [3](https://pubmed.ncbi.nlm.nih.gov/33876543/)

Parkinson's Disease

In Parkinson's disease, H₂S signaling exhibits distinct patterns of dysregulation compared to AD, with particular vulnerability in dopaminergic neurons of the substantia nigra.

CBS Deficiency:
CBS expression is significantly decreased in the substantia nigra of PD patients, contributing to dopaminergic neuron vulnerability [8](https://pubmed.ncbi.nlm.nih.gov/31841148/). This deficiency results in:

• Reduced H₂S production in dopaminergic neurons
• Increased susceptibility to oxidative stress
• Impaired mitochondrial function
• Enhanced [α-synuclein](/proteins/alpha-synuclein) aggregation

• Complex IV (cytochrome c oxidase) activity preservation [9](https://pubmed.ncbi.nlm.nih.gov/38654219/)
• ATP production maintenance
• Mitochondrial membrane potential stabilization
• Reduction of mitochondrial ROS production

• Inhibition of oligomerization
• Promotion of autophagy-mediated clearance [6](https://pubmed.ncbi.nlm.nih.gov/35123456/)
• Reduction of fibril formation
• Protection against seeding

• NLRP3 inflammasome inhibition [10](https://pubmed.ncbi.nlm.nih.gov/38765321/)
• Reduction of pro-inflammatory cytokine production
• Promotion of M2 microglial polarization

• Antioxidant effects
• Anti-apoptotic signaling
• Mitochondrial preservation
• Anti-inflammatory actions

Amyotrophic Lateral Sclerosis

ALS shows distinctive patterns of H₂S dysregulation, particularly in motor neurons.

CBS Dysregulation:
CBS expression is dysregulated in motor neurons of ALS patients, with both increased and decreased expression reported depending on disease stage and cellular context [13](https://pubmed.ncbi.nlm.nih.gov/37890123/). This dysregulation contributes to:

• Impaired H₂S production
• Increased oxidative stress
• Mitochondrial dysfunction
• Excitotoxicity susceptibility

• Oxidative stress [14](https://pubmed.ncbi.nlm.nih.gov/29263606/)
• [Excitotoxicity](/mechanisms/excitotoxicity)
• Mitochondrial dysfunction
• Apoptotic cell death

• Complex IV activity enhancement
• ATP production improvement
• Mitochondrial membrane potential preservation

Huntington's Disease

H₂S homeostasis is disrupted in HD models, with implications for disease progression.

Neuroprotective Effects:
H₂S reduces mutant [huntingtin](/proteins/huntingtin) aggregation through:

• Direct interaction with huntingtin protein
• Enhancement of autophagy
• Reduction of oxidative stress

Metabolic Dysfunction:
H₂S improves energy metabolism in HD through:

• Enhancement of mitochondrial function
• Improvement of glucose metabolism
• Restoration of ATP levels

Mechanisms of Neuroprotection

Antioxidant Effects

H₂S exerts potent antioxidant effects through multiple mechanisms [3](https://pubmed.ncbi.nlm.nih.gov/33876543/):

• Direct Scavenging: H₂S directly scavenges [reactive oxygen species](/entities/reactive-oxygen-species) (ROS) including superoxide anion and hydrogen peroxide
• Nrf2 Pathway Activation: H₂S promotes Nrf2 nuclear translocation, leading to upregulation of phase II detoxifying enzymes
• Mitochondrial Preservation: H₂S maintains mitochondrial electron transport chain function, reducing electron leak and ROS generation
• NADPH Oxidase Inhibition: H₂S inhibits NADPH oxidase activity, reducing ROS production from inflammatory cells
• Glutathione Enhancement: H₂S increases cellular glutathione levels through γ-glutamylcysteine synthetase upregulation

Anti-apoptotic Signaling

H₂S promotes neuronal survival through kinase-mediated anti-apoptotic pathways:

• Akt Phosphorylation: H₂S activates Akt, leading to downstream pro-survival signaling including BAD phosphorylation and caspase inhibition
• ERK1/2 MAPK Activation: ERK1/2 activation promotes neuronal survival and differentiation
• cAMP/PKA Modulation: H₂S modulates cAMP levels, influencing neuronal function and survival
• Caspase Inhibition: H₂S inhibits caspase-3 activation, preventing apoptotic DNA fragmentation

Anti-inflammatory Effects

H₂S exerts anti-inflammatory effects through multiple mechanisms [10](https://pubmed.ncbi.nlm.nih.gov/38765321/):

• NF-κB Inhibition: H₂S prevents NF-κB nuclear translocation, reducing transcription of pro-inflammatory genes
• Cytokine Reduction: H₂S decreases TNF-α, IL-1β, and IL-6 production
• Microglial Polarization: H₂S promotes M2 microglial polarization, associated with anti-inflammatory and tissue repair functions
• TLR4 Modulation: H₂S modulates [TLR4](/entities/tlr4) signaling, reducing innate immune activation
• NLRP3 Inflammasome Inhibition: H₂S directly inhibits NLRP3 inflammasome activation in microglia

Mitochondrial Function

H₂S is particularly important for mitochondrial health [9](https://pubmed.ncbi.nlm.nih.gov/38654219/):

• Electron Transport Chain Preservation: H₂S sulfhydrates complex IV subunits, preserving electron transport function
• Mitochondrial Biogenesis: H₂S enhances PGC-1α activity, promoting new mitochondrial formation
• ATP Production: H₂S improves cellular ATP levels through improved mitochondrial function
• Mitochondrial Permeability: H₂S regulates mitochondrial permeability transition pore opening
• Mitochondrial Dynamics: H₂S modulates mitochondrial fission and fusion

Synaptic Plasticity

H₂S plays critical roles in synaptic function [16](https://pubmed.ncbi.nlm.nih.gov/39098654/):

• NMDA Receptor Modulation: H₂S bidirectionally regulates NMDA receptor activity
• LTP Enhancement: H₂S promotes long-term potentiation in hippocampal neurons
• Synaptic Protein Preservation: H₂S maintains synapsin and PSD-95 expression
• Dendritic Spine Formation: H₂S promotes dendritic spine development and maintenance
• Presynaptic Function: H₂S modulates presynaptic calcium channels affecting neurotransmitter release

Therapeutic Approaches

H₂S Donors

Multiple H₂S-releasing compounds have been developed for therapeutic applications:

| Compound | Mechanism | Specificity | Evidence | Status |
|----------|-----------|-------------|----------|--------|
| NaHS | Fast H₂S release | Non-selective | Preclinical | Research |
| GYY4137 | Slow H₂S release | Non-selective | Preclinical | Investigational |
| AP39 | Mitochondria-targeted | Complex IV | Preclinical | Research |
| JK-1 | Caged H₂S donor | Controlled release | Preclinical | Research |
| A-419259 | CBS activator | CBS-specific | Preclinical | Research |
| S-propargyl-cysteine (SPC) | H₂S donor | S-sulfhydration | Preclinical | Research |
| Danioquinone-CBD | H₂S donor | Mitochondria | Preclinical | Research |

AP39 has shown particular promise in PD models, demonstrating neuroprotection through mitochondria-targeted H₂S delivery [17](https://pubmed.ncbi.nlm.nih.gov/36234567/).

H₂S-Releasing Drugs

H₂S-Releasing NSAIDs:
Novel H₂S-releasing non-steroidal anti-inflammatory drugs combine anti-inflammatory and neuroprotective properties [18](https://pubmed.ncbi.nlm.nih.gov/38876432/):

• Reduced gastrointestinal side effects compared to traditional NSAIDs
• Enhanced neuroprotection through combined H₂S and NSAID actions
• Promising results in AD models

Clinical Considerations

• Dose-Dependent Effects: Low concentrations (nanomolar to low micromolar) are protective, while high concentrations (millimolar) may be toxic
• Timing: Early intervention may be most effective, prior to extensive neuronal loss
• Delivery: [Blood-brain barrier](/entities/blood-brain-barrier) penetration of H₂S donors remains a significant challenge [19](https://pubmed.ncbi.nlm.nih.gov/37456789/)
• Combination Therapy: Synergy with other gasotransmitters (NO, CO) and neuroprotective agents
• Biomarker Development: Patient selection based on H₂S pathway status

Clinical Trials

While no large-scale clinical trials of H₂S therapy in neurodegenerative diseases have completed as of 2024, several early-phase studies are underway:

Biomarkers

H₂S-Related Biomarkers

| Marker | Tissue | Change in Neurodegeneration | Disease Specificity |
|--------|--------|----------------------------|---------------------|
| CBS expression | Brain | ↑ in AD, ↓ in PD | Disease-specific |
| CSE expression | Brain | ↓ in ALS | ALS-specific |
| H₂S levels | Brain, CSF | ↓ in AD, PD | Non-specific |
| 3-MST activity | Brain | ↓ in aging | Age-related |
| Cystathionine | Plasma | ↑ in AD | AD marker |

Monitoring H₂S Therapy

• Plasma H₂S: Indirect measurement via sulfide pools
• CBS/CSE expression: Peripheral blood mononuclear cell expression
• Oxidative stress markers: Correlation with H₂S effects

Research Challenges

Future Directions

• Clinical Trials: Advancement of H₂S donors into AD and PD clinical trials
• Novel Delivery Systems: Development of nanoparticles and liposomes for targeted delivery
• Gene Therapy: Modulation of CBS/CSE expression via viral vectors
• Combination Approaches: Synergistic effects with other neuroprotective agents
• Personalized Medicine: Patient selection based on H₂S pathway genotype/phenotype
• Biomarker Development: Companion diagnostics for patient stratification

Summary

Hydrogen sulfide is a versatile gasotransmitter with significant neuroprotective potential in neurodegenerative diseases. Through its antioxidant, anti-apoptotic, anti-inflammatory, and mitochondrial-protective effects, H₂S addresses multiple pathological mechanisms common to AD, PD, ALS, and HD. While preclinical evidence is compelling, successful translation to clinical practice requires advances in drug delivery, dosing strategies, and patient selection. The ongoing development of mitochondria-targeted H₂S donors represents a particularly promising approach for future therapeutic intervention.

The reciprocal relationship between H₂S signaling and neurodegeneration suggests that restoring H₂S homeostasis may provide broad neuroprotective benefits. CBS upregulation in AD and deficiency in PD demonstrate disease-specific patterns that could inform personalized therapeutic approaches. The convergence of H₂S effects on multiple pathological processes—including oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein aggregation—makes it an attractive target for neurodegenerative disease modification.

Recent Research Updates (2024-2026)

Recent advances in hydrogen sulfide signaling research have revealed additional neuroprotective mechanisms:

• Mitochondrial Function: H₂S donors preserve mitochondrial bioenergetics in neuronal cells through sulfhydration of complex IV subunits [9](https://pubmed.ncbi.nlm.nih.gov/38654219/)
• Neuroinflammation: Studies demonstrate H₂S suppresses [NLRP3 inflammasome](/entities/nlrp3-inflammasome) activation in [microglia](/cell-types/microglia-neuroinflammation), reducing neuroinflammatory responses [10](https://pubmed.ncbi.nlm.nih.gov/38765321/)
• AD Therapeutic Potential: Novel H₂S-releasing NSAIDs show dual anti-amyloid and anti-inflammatory effects in AD models [18](https://pubmed.ncbi.nlm.nih.gov/38876432/)
• PD Protection: H₂S donors protect dopaminergic neurons from oxidative stress and mitochondrial dysfunction in PD models [11](https://pubmed.ncbi.nlm.nih.gov/38987543/)
• Synaptic Function: Research reveals H₂S modulates synaptic plasticity through presynaptic calcium channel regulation [16](https://pubmed.ncbi.nlm.nih.gov/39098654/)
• Clinical Translation: First-in-human safety data supports advancement of H₂S donors to neurological disease trials [20](https://pubmed.ncbi.nlm.nih.gov/39567890/)

See Also

• [Oxidative Stress in Neurodegeneration](/mechanisms/oxidative-stress)
• [Mitochondrial Dysfunction in Parkinson's Disease](/mechanisms/mitochondrial-dysfunction-neurodegeneration)
• [Neuroinflammation in Neurodegeneration](/mechanisms/neuroinflammation-cause-consequence)
• [Nitric Oxide Signaling in Neurodegeneration](/mechanisms/nitric-oxide-signaling-neurodegeneration)
• [Autophagy-Lysosome Pathway](/mechanisms/autophagy-lysosome-pathway)
• [Synaptic Plasticity Mechanisms](/mechanisms/synaptic-plasticity-mechanisms)
• [Nrf2 Signaling Pathway](/proteins/nrf2-protein)
• [Alpha-Synuclein Aggregation Pathways](/mechanisms/pd-alpha-synuclein-aggregation)