論文 - 詳細
| RRC ID | 46542 |
|---|---|
| 著者 | Yuan Y, Cao P, Smith MA, Kramp K, Huang Y, Hisamoto N, Matsumoto K, Hatzoglou M, Jin H, Feng Z. |
| タイトル | Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans. |
| ジャーナル | PLoS One |
| 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. |
| 巻・号 | 6(8) |
| ページ | e22354 |
| 公開日 | 2011-1-1 |
| DOI | 10.1371/journal.pone.0022354 |
| PII | PONE-D-10-06514 |
| PMID | 21857923 |
| PMC | PMC3153934 |
| MeSH | Animals Animals, Genetically Modified Blotting, Western Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Line, Tumor Cells, Cultured Dopaminergic Neurons / metabolism* Dopaminergic Neurons / pathology Endoplasmic Reticulum Chaperone BiP Endoplasmic Reticulum Stress* Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism HEK293 Cells Heat-Shock Proteins / genetics Heat-Shock Proteins / 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 Protein Serine-Threonine Kinases / metabolism* RNA Interference Signal Transduction p38 Mitogen-Activated Protein Kinases / metabolism |
| IF | 2.74 |
| 引用数 | 48 |
| WOS 分野 | NEUROSCIENCES |
| リソース情報 | |
| 線虫 | tm1898 |