Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson's disease

Johnson, William M.; Yao, Chen; Siedlak, Sandra L.; Wang, Wenzhang; Zhu, Xiongwei; Caldwell, Guy A.; Wilson-Delfosse, Amy L.; Mieyal, John J.; Chen, Shu G.

doi:10.1093/hmg/ddu542

Cited by 36 publications

(63 citation statements)

References 45 publications

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“…Secondary antibodies were incubated for 1 h in 5% milk in TBST, washed three times in TBST and developed using ECL (Pierce). Antibodies used included anti-actin (Sigma), anti-DJ-1 (Abcam) and anti-Grx1 [20]. …”

Section: Methodsmentioning

confidence: 99%

“…Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme in the cell, restoring the protein-SH and its function [2]. Grx1 has been shown to mediate neuronal protection both in vitro and in vivo [19, 20, 21, 22]. We recently reported evidence that PD patients have diminished levels of Grx1 specifically within the remaining dopaminergic neurons of the midbrain compared to controls [20].…”

Section: Introductionmentioning

confidence: 99%

“…Grx1 has been shown to mediate neuronal protection both in vitro and in vivo [19, 20, 21, 22]. We recently reported evidence that PD patients have diminished levels of Grx1 specifically within the remaining dopaminergic neurons of the midbrain compared to controls [20]. Further we found that Caenorhabditis elegans (C. elegans) lacking the homolog of Grx1 displayed exacerbated losses of dopamine-dependent behavior and dopaminergic neurons in models of both familial and sporadic PD [20].…”

Section: Introductionmentioning

confidence: 99%

“…We recently reported evidence that PD patients have diminished levels of Grx1 specifically within the remaining dopaminergic neurons of the midbrain compared to controls [20]. Further we found that Caenorhabditis elegans (C. elegans) lacking the homolog of Grx1 displayed exacerbated losses of dopamine-dependent behavior and dopaminergic neurons in models of both familial and sporadic PD [20]. Thus, it appears that Grx1 mediates protection of dopaminergic neurons in vitro and in vivo , however the downstream molecular mechanism(s) that accomplish this protection remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

et al. 2016

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Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH; and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in C. elegans, however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx−/− mice we provide evidence that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents; and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homolog in a C. elegans in vivo model of PD. Therefore; our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

et al. 2016

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“…Still little was known about the neuroprotective role of Grx1 in vivo and its implications for PD in humans. These limitations were addressed in our recent study [44] which is highlighted by this commentary.…”

Section: Focus On the Neuroprotective Role Of The Glutaredoxin Enzymementioning

confidence: 88%

The Roles of Redox Enzymes in Parkinson’s Disease: Focus on Glutaredoxin

Johnson

Wilson-Delfosse

Chen

et al. 2015

Ther Targets Neurol Dis

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Parkinson's disease (PD) results from the loss of dopaminergic neurons in the substantia nigra portion of the midbrain, and represents the second most common neurodegenerative disease in the world. Although the etiology of PD is currently unclear, oxidative stress and redox dysfunction are generally understood to play key roles in PD pathogenesis and progression. Aging and environmental factors predispose cells to adverse effects of redox changes. In addition to these factors, genetic mutations linked to PD have been observed to disrupt the redox balance. Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with autosomal dominant PD, and several of these mutations have also been shown to increase the levels of reactive oxygen species in cells. Anti-oxidant proteins are necessary to restore the redox balance and maintain cell viability. Over the past decade studies have started to demonstrate the critical importance for redox proteins mediating neuronal protection in models of PD. This commentary briefly describes some of the factors hypothesized to contribute to PD, specifically regarding the redox changes that occur in PD. Dysregulation of redox proteins in PD is highlighted by some of the work detailing the roles of peroxiredoxin-3 and thioredoxin-1 in models of PD. In an attempt to generate novel therapies for PD, several potent inhibitors of LRRK2 have been developed. The use of these compounds, both as tools to understand the biology of LRRK2 and as potential therapeutic strategies is also discussed. This mini-review then provides a historical prospective on the discovery and characterization of glutaredoxin (Grx1), and briefly describes current understanding of the role of Grx1 in PD. The review concludes by highlighting our recent publication describing the novel role for Grx1 in mediating dopaminergic neuronal protection both in vitro and in vivo.

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Glutaredoxin 1 Downregulation in the Substantia Nigra Leads to Dopaminergic Degeneration in Mice

et al. 2020

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A BS TRACT: Background: Parkinson's disease (PD) is characterized by a severe loss of the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Perturbation of protein thiol redox homeostasis has been shown to play a role in the dysregulation of cell death and cell survival signaling pathways in these neurons. Glutaredoxin 1 (Grx1) is a thiol/disulfide oxidoreductase that catalyzes the deglutathionylation of proteins and is important for regulation of cellular protein thiol redox homeostasis. Objectives: We evaluated if the downregulation of Grx1 could lead to dopaminergic degeneration and PDrelevant motor deficits in mice. Methods: Grx1 was downregulated unilaterally through viral vector-mediated transduction of short hairpin RNA against Grx1 into the SNpc. Behavioral assessment was performed through rotarod and elevated body swing test. Stereological analysis of tyrosine hydroxylase-positive and Nissl-positive neurons was carried out to evaluate neurodegeneration. Results: Downregulation of Grx1 resulted in contralateral bias of elevated body swing and reduced latency to fall off, accelerating rotarod. This was accompanied by a loss of tyrosine hydroxylase-positive neurons in the SNpc and their DA projections in the striatum. Furthermore, there was a loss Nissl-positive neurons in the SNpc, indicating cell death. This was selective to the SNpc neurons because DA neurons in the ventral tegmental area were unaffected akin to that seen in human PD. Furthermore, Grx1 mRNA expression was substantially decreased in the SNpc from PD patients. Conclusions: Our study indicates that Grx1 is critical for the survival of SNpc DA neurons and that it is downregulated in human PD.

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Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson's disease

Cited by 36 publications

References 45 publications

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

The Roles of Redox Enzymes in Parkinson’s Disease: Focus on Glutaredoxin

Glutaredoxin 1 Downregulation in the Substantia Nigra Leads to Dopaminergic Degeneration in Mice

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