Investigating Convergent Actions of Genes Linked to Familial Parkinson’s Disease

Abstract

Background: Mutations in LRRK2 are among the most frequent genetic changes identified in Parkinson’s disease (PD), but how LRRK2 contributes to the pathophysiology of PD is not known. Objectives: To investigate how expressing wild-type or G2019S LRRK2 modifies cellular responses to rotenone, a mitochondrial toxin. Methods: We investigated the vulnerability to mitochondrial toxins in Caenorhabditis elegans expressing wild-type or G2019S LRRK2. Results: We observed a powerful role for LRRK2 in mitochondrial biology. Overexpressing LRRK2 strongly protects C. elegans against rotenone toxicity. The G2019S LRRK2 construct also protected LRRK2 against rotenone, but to a lesser degree than wild-type LRRK2. Knockdown of lrk-1 potentiated rotenone toxicity. Conclusions: These data suggest that LRRK1/2 regulate mitochondrial physiology.

Caenorhabditis elegans: An Emerging Model System for Pesticide Neurotoxicity

“…The role of complex I in preventing rotenone toxicity has been demonstrated in C. elegans, as strains with mutations in mitochondrial complex I showed increased vulnerability to the toxicity of rotenone [3]. Worms containing modified genes associated with Parkinson's disease were also more susceptible to oxidative damage due to rotenone exposure [141,142]. This illustrates the importance of these genes in the prevention of rotenone toxicity and oxidative stress in dopaminergic neurons.…”

Update on the Functional Biology of Lrrk2

“…LRK-1-knockout worms have a chemosensory deficit, which is interesting since marked olfactory dysfunction is a frequent and early abnormality in PD. C. elegans expressing human WT Lrrk2 have a longer lifespans than G2019S or nontransgenic worms [74]. Human Lrrk2 WT worms also show significantly less vulnerability to the toxin rotenone compared with nontransgenic worms, and surprisingly, G2019S worms also had less vulnerability to rotenone.…”

Modeling LRRK2 Parkinsonism

“…Transgenic worms have been created by either overexpressing wild-type (WT) LRK-1 and/or comparable mutant LRK-1 or by overexpressing human WT or mutant LRRK2 with fluorescent tags (Sakaguchi-Nakashima et al, 2007;Samann et al, 2009) driven by tissuespecific promoters whereas others have over-expressed human LRRK2 WT and pathogenic mutants via the dopamine neuron-specific DAT promoters (Saha et al, 2009;Wolozin et al, 2008;Yao et al, 2010). Over-expression of endogenous WT and mutant LRK-1 in neurons resulted in axon guidance defects and embryonic lethality (Samann et al, 2009).…”

“…Over-expression of endogenous WT and mutant LRK-1 in neurons resulted in axon guidance defects and embryonic lethality (Samann et al, 2009). Surprisingly, worms expressing human LRRK2 had increased longevity and reduced vulnerability to mitochondrial toxicity, with human WT LRRK2 offering more protection than mutant G2019S, R1441C or R1441C kinase dead LRRK2 (Saha et al, 2009;Wolozin et al, 2008). Despite this protection, transgenic LRRK2 WT and G2019S worms exhibited DA neuron degeneration and decreased dopamine levels, with G2019S mutants exhibiting more severe phenotypes (Saha et al, 2009).…”