Oxidative stress mechanisms underlying Parkinson's disease-associated neurodegeneration in C. elegans

Abstract

Oxidative stress is thought to play a significant role in the development and progression of neurodegenerative diseases. Although it is currently considered a hallmark of such processes, the interweaving of a multitude of signaling cascades hinders complete understanding of the direct role of oxidative stress in neurodegeneration. In addition to its extensive use as an aging model, some researchers have turned to the invertebrate model Caenorhabditis elegans (C. elegans) in order to further investigate molecular mediators that either exacerbate or protect against reactive oxygen species (ROS)-mediated neurodegeneration. Due to their fully characterized genome and short life cycle, rapid generation of C. elegans genetic models can be useful to study upstream markers of oxidative stress within interconnected signaling pathways. This report will focus on the roles of C. elegans homologs for the oxidative stress-associated transcription factor Nrf2, as well as the autosomal recessive, early-onset Parkinson's disease (PD)-associated proteins Parkin, DJ-1, and PINK1, in neurodegenerative processes.

Figure 1

Arrowheads indicate the four dopaminergic cephalic (CEP) neurons in the head of the worm, with dendritic processes extending down to the tip of the nose.

Figure 2

Decreased lifespan in pdr-1 KO worms is exacerbated by Mn exposure. Two thousand five hundred L1 worms were treated with MnCl₂ for 30 min, washed and then plated onto NGM plates spread with OP50 bacteria. Twenty worms were plated in triplicates per group. Worms were assessed for survival each day, and transferred to fresh plates every other day, until all worms had died. Wildtype worms: N2 strain; pdr-1 KO: pdr-1 (gk448) deletion. Compared to untreated WT animals, the other groups show a statistically significant leftward shift in lifespan (logrank test, p < 0.001), with one-way ANOVA analysis on median survival finding a significantly decreased lifespan in treated WT worms (p < 0.001) that is enhanced in the pdr-1 KO animals (p < 0.001).