S5-3 Can hydrogen sulfide be used to treat neurodegenerative diseases?

Abstract

Hydrogen sulfide (H2S) was reported to be cytoprotective in various biological systems. We investigated the neuroprotective function of H2S in different neurodegenerative disease models. In neurotoxin-induced Parkinson’s disease animal models, we found that NaHS, an H2S donor, reversed dopaminergic neuron loss via its anti-oxidant, anti-inflammatory and anti-apoptotic effects. We also tested the beneficial effects of H2S in Alzheimer’s disease animal models. A β is the major component of the neuritic plaques and is generated from β-amyloid precursor protein (APP). We found that NaHS inhibited amyloid β formation by downregulation of APP expression and suppression of the activity of β-secretase, a β-site APP cleaving enzyme 1 (BACE1). The tau protein is a neuronal microtubule-associated protein. Abnormal accumulation of Tau causes paired helical fragments (PHF). It was found that NaHS inhibited tau protein hyperphosphorylation, polymerization and aggregation. Tau K18 contains the 4 microtubule binding repeats and consists of 2 cysteine residues (C291, C322). To study the molecular mechanisms, we constructed WT, C291S, C322S and C291S/C322S mutant K18. ThT polymerization assay showed that NaHS reduced the polymerization of K18 induced by heparin. C291S/C322S attenuated the protective effect of NaHS against Tau polymerization. In addition, NaHS induced S-sulfhydration of WT-K18, but had no effect on C291S/C322S mutants. These data suggest that H2S may reduce tau polymerization by S-sulfhydration of its cysteine residues. Taken together, our study suggests that H2S might be a potential therapeutic target/agent for neurodegenerative diseases.