title: The roles of redox enzymes in Parkinson's disease: Focus on glutaredoxin.
abstract: Parkinson's disease (PD) results from the loss of dopaminergic neurons in thesubstantia nigraportion 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 bothin vitroandin vivo.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Wilson-Delfosse
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Shu G
authors.initials: SG
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA ; Louis B. Stokes Veterans Affairs Medical Research Center, Cleveland, OH 44106, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mieyal
keywords: C. elegans; Glutaredoxin; LRRK2; Parkinson’s disease; redox