Protein glutathionylation is a redox-mediated posttranslational modification that regulates the function of target proteins by conjugating glutathione with a cysteine thiol group on the target proteins. Protein glutathionylation has several biological functions such as regulation of metabolic pathways, calcium homeostasis, signal transduction, remodeling of cytoskeleton, inflammation, and protein folding. However, the exact role and mechanism of glutathionylation during irreversible oxidative stress has not been completely defined. Irreversible oxidative damage is implicated in a number of neurological disorders. Here, we discuss and highlight the most recent findings and several evidences for the association of glutathionylation with neurodegenerative diseases and the role of glutathionylation of specific proteins in the pathogenesis of neurodegenerative diseases. Understanding the important role of glutathionylation in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions.

The omega class glutathione S-transferases (GSTOs) are multifunctional enzymes involved in cellular defense and have distinct structural and functional characteristics, which differ from those of other GSTs. Previous studies provided evidence for the neuroprotective effects of GSTOs. However, the molecular mechanisms underpinning the neuroprotective functions of GSTOs have not been fully elucidated. Recently, our genetic and molecular studies using the Drosophila system have suggested that GstO1 has a protective function against H2O2-induced neurotoxicity by regulating the MAPK signaling pathway, and GstO2 is required for the activation of mitochondrial ATP synthase in the Drosophila neurodegenerative disease model. The comprehensive understanding of various neuroprotection mechanisms of Drosophila GstOs from our studies provides valuable insight into the neuroprotective functions of GstOs in vivo. In this review, we briefly introduce recent studies and summarize the novel biological functions and mechanisms underpinning neuroprotective effects of GstOs in Drosophila.

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

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Fused in sarcoma (FUS) is a DNA/RNA‐binding protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. The exact molecular mechanisms by which FUS results in neurotoxicity have not yet been fully elucidated. Here, we found that parkin is a genetic suppressor of defective phenotypes induced by exogenous human wild type FUS in Drosophila. Although parkin overexpression did not modulate the FUS protein expression level, the locomotive defects in FUS‐expressing larvae and adult flies were rescued by parkin expression. We found that FUS expression in muscle tissues resulted in a reduction of the levels and assembly of mitochondrial complex I and III subunits, as well as decreased ATP. Remarkably, expression of parkin suppressed these mitochondrial dysfunctions. Our results indicate parkin as a neuroprotective regulator of FUS‐induced proteinopathy by recovering the protein levels of mitochondrial complexes I and III. Our findings on parkin‐mediated neuroprotection may expand our understanding of FUS‐induced ALS pathogenesis.