title: Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson's disease.
abstract: Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic neurons. Although the etiology of PD remains incompletely understood, oxidative stress has been implicated as an important contributor in the development of PD. Oxidative stress can lead to oxidation and functional perturbation of proteins critical to neuronal survival. Glutaredoxin 1 (Grx1) is an evolutionally conserved antioxidant enzyme that repairs protein oxidation by reversing the oxidative modification of cysteine known as S-glutathionylation. We aimed to explore the regulatory role of Grx1 in PD. We first examined the levels of Grx1 in postmortem midbrain samples from PD patients, and observed that Grx1 content is decreased in PD, specifically within the dopaminergic neurons. We subsequently investigated the potential role of Grx1 deficiency in PD pathogenesis by examining the consequences of loss of the Caenorhabditis elegans Grx1 homolog in well-established worm models of familial PD caused by overexpression of pathogenic human LRRK2 mutants G2019S or R1441C. We found that loss of the Grx1 homolog led to significant exacerbation of the neurodegenerative phenotype in C. elegans overexpressing the human LRRK2 mutants. Re-expression in the dopaminergic neurons of the active, but not a catalytically inactive form of the Grx1 homolog rescued the exacerbated phenotype. Loss of the Grx1 homolog also exacerbated the neurodegenerative phenotype in other C. elegans models, including overexpression of human α-synuclein and overexpression of tyrosine hydroxylase (a model of sporadic PD). Therefore, our results reveal a novel neuroprotective role of glutaredoxin against dopaminergic neurodegeneration in models of familial and sporadic PD.
authors.affiliation: Department of Pharmacology and.
authors.forename: William M
authors.initials: WM
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Wenzhang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.affiliation: Department of Pharmacology and.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Wilson-Delfosse
authors.affiliation: Department of Pharmacology and Louis B. Stokes Veterans Affairs Medical Research Center, Cleveland, OH 44106, USA jjm5@case.edu shu.chen@case.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mieyal
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA, jjm5@case.edu shu.chen@case.edu.
authors.forename: Shu G
authors.initials: SG
authors.lastname: Chen
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D002470:Cell Survival; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D054477:Glutaredoxins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008636:Mesencephalon / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D054477:Glutaredoxins; D015801:Helminth Proteins; D012333:RNA, Messenger; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D003545:Cysteine