Wild-type LRRK2 but not its mutant attenuates stress-induced cell death via ERK pathway.
Leucine-rich repeat kinase 2 (LRRK2) is a recently identified gene that, when mutated at specific locations, results in the onset of parkinsonian symptoms with clinical features indistinguishable from idiopathic Parkinson's disease. Based on structural and domain analysis, LRRK2 is predicted to function as a stress-responsive protein scaffold mediating the regulation of mitogen activating protein kinase (MAPK) pathways. Consistent with this notion, our results supported the notion that expression of wild-type LRRK2 but not Y1699C or G2019S mutants enhanced the tolerance of HEK293 and SH-SY5Y cells towards H(2)O(2)-induced oxidative stress. This increase in stress tolerance was dependent on the presence of the kinase domain of the LRRK2 gene and manifested through the activation of the ERK pathway. Collectively, our results indicated that cells expressing LRRK2 mutants suffer a loss of protection normally derived from wild-type LRRK2, making them more vulnerable to oxidative stress.
Liou
Anthony K F
AK
Pittsburgh Institute for Neurodegenerative Diseases, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA. lioukf@upmc.edu
Leak
Rehana K
RK
Li
Lihua
L
Zigmond
Michael J
MJ
D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases