Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans.

Abstract	Mutation of leucine-rich repeat kinase 2 (LRRK2) is the leading genetic cause of Parkinson's Disease (PD), manifested as age-dependent dopaminergic neurodegeneration, but the underlying molecular mechanisms remain unclear. Multiple roles of LRRK2 may contribute to dopaminergic neurodegeneration. Endoplasmic reticulum (ER) stress has also been linked to PD pathogenesis, but its interactive mechanism with PD genetic factors is largely unknown. Here, we used C. elegans, human neuroblastoma cells and murine cortical neurons to determine the role of LRRK2 in maintaining dopaminergic neuron viability. We found that LRRK2 acts to protect neuroblastoma cells and C. elegans dopaminergic neurons from the toxicity of 6-hydroxydopamine and/or human α-synuclein, possibly through the p38 pathway, by supporting upregulation of GRP78, a key cell survival molecule during ER stress. A pathogenic LRRK2 mutant (G2019S), however, caused chronic p38 activation that led to death of murine neurons and age-related dopaminergic-specific neurodegeneration in nematodes. These observations establish a critical functional link between LRRK2 and ER stress.
Authors	Yiyuan Yuan, Pengxiu Cao, Mark A Smith, Kristopher Kramp, Ying Huang, Naoki Hisamoto, Kunihiro Matsumoto, Maria Hatzoglou, Hui Jin, Zhaoyang Feng
Journal	PloS one (PLoS One) Vol. 6 Issue 8 Pg. e22354 ( 2011) ISSN: 1932-6203 [Electronic] United States
PMID	21857923 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Caenorhabditis elegans Proteins Endoplasmic Reticulum Chaperone BiP HSPA5 protein, human Heat-Shock Proteins Hspa5 protein, mouse Green Fluorescent Proteins Oxidopamine LRK-1 protein, C elegans LRRK2 protein, human Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Lrrk2 protein, mouse Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinases Pmk-1 protein, C elegans p38 Mitogen-Activated Protein Kinases
Topics	Animals Animals, Genetically Modified Blotting, Western Caenorhabditis elegans (genetics, metabolism) Caenorhabditis elegans Proteins (genetics, metabolism) Cell Line, Tumor Cells, Cultured Dopaminergic Neurons (metabolism, pathology) Endoplasmic Reticulum Chaperone BiP Endoplasmic Reticulum Stress Green Fluorescent Proteins (genetics, metabolism) HEK293 Cells Heat-Shock Proteins (genetics, metabolism) Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Mice Microscopy, Confocal Mitogen-Activated Protein Kinases (metabolism) Mutation Nerve Degeneration (chemically induced) Oxidopamine Protein Serine-Threonine Kinases (genetics, metabolism) RNA Interference Signal Transduction p38 Mitogen-Activated Protein Kinases (metabolism)

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