Investigating convergent actions of genes linked to familial Parkinson's disease.
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.


OBJECTIVE
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.
Wolozin
Benjamin
B
Department of Pharmacology, Boston University School of Medicine, Boston, Mass. 02118-2526, USA. bwolozin@bu.edu
Saha
Shamol
S
Guillily
Maria
M
Ferree
Andrew
A
Riley
Misha
M
D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D008040:Genetic Linkage / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D012402:Rotenone / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D029742:Caenorhabditis elegans Proteins; D012402:Rotenone; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases