Loss of redoxin proteins exacerbates LRRK2‐mediated Parkinson's disease phenotype in C. elegans

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Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, and oxidative stress is considered a major contributor to PD pathogenesis. Recently, we and others found that pathogenic mutations in the leucine rich repeat kinase 2 (LRRK2) gene linked to familial PD promote increased ROS generation in model neuronal cells in culture.The redoxin family of proteins, including peroxiredoxin and glutaredoxin, provides defenses against oxidative stress through peroxide‐scavenging and protein repair mechanisms. Hence, we hypothesized that loss of Prdx‐3 or Grx1 would result in exacerbation of the mutant LRRK2‐dependent PD phenotype.Previously we demonstrated that expression of mutant human LRRK2 in dopaminergic neurons of C. elegans resulted in impaired dopamine‐dependent behavior and age‐dependent loss of dopaminergic neurons. Here we report that mutant LRRK2 expression concomitant with embryonic knockout of Prdx‐3 or Grx1 exacerbates the impairment of dopamine‐dependent movement and increases the loss of dopaminergic neurons. Notably, knockout of Prdx‐3 alone results in a PD phenotype. Thus, Grx1 and Prdx‐3 may act as novel PD suppressors in vivo. Current studies are focused on molecular mechanisms by which Grx1 and Prdx‐3 may mediate neuronal protection in vivo. Supported in part by NIH grants 5R21NS073170 (SGC & ALW) and T32GM008803 (WMJ), and VA grant BX000290 (JJM).