RRC ID 31380
Author Johnson WM, Yao C, Siedlak SL, Wang W, Zhu X, Caldwell GA, Wilson-Delfosse AL, Mieyal JJ, Chen SG.
Title Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson's disease.
Journal Hum. Mol. Genet.
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.
Volume 24(5)
Pages 1322-35
Published 2015-3-1
DOI 10.1093/hmg/ddu542
PII ddu542
PMID 25355420
PMC PMC4321441
MeSH Animals Caenorhabditis elegans / genetics* Cell Survival Cysteine / metabolism Disease Models, Animal Dopaminergic Neurons / metabolism Evolution, Molecular Gene Expression Regulation Glutaredoxins / deficiency Glutaredoxins / genetics* Glutaredoxins / metabolism Helminth Proteins / genetics Helminth Proteins / metabolism* Homeostasis Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Mesencephalon / metabolism Oxidative Stress Parkinson Disease / genetics* Phenotype Protein-Serine-Threonine Kinases / genetics Protein-Serine-Threonine Kinases / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism Tyrosine 3-Monooxygenase / genetics Tyrosine 3-Monooxygenase / metabolism alpha-Synuclein / genetics alpha-Synuclein / metabolism
IF 4.902
Times Cited 12
WOS Category GENETICS & HEREDITY BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
C.elegans tm4634