| RRC ID |
17679
|
| 著者 |
Mori A, Yamashita S, Uchino K, Suga T, Ikeda T, Takamatsu K, Ishizaki M, Koide T, Kimura E, Mita S, Maeda Y, Hirano T, Uchino M.
|
| タイトル |
Derlin-1 overexpression ameliorates mutant SOD1-induced endoplasmic reticulum stress by reducing mutant SOD1 accumulation.
|
| ジャーナル |
Neurochem Int
|
| Abstract |
Unfolded protein responses, including induction of stress sensor kinases, chaperones, and apoptotic mediators, are involved in the familial amyotrophic lateral sclerosis (ALS) model related to mutant Cu/Zn superoxide dismutase (SOD1) and sporadic ALS. We hypothesized that the endoplasmic reticulum-resident factor Derlin-1 plays a pivotal role in the regulation of misfolded proteins evoked by mutant SOD1. We show that Derlin-1 overexpression reduced mutant SOD1-induced cell toxicity and increased cell viability by suppressing the activation of the ER stress pathway factors: immunoglobulin-binding protein, activating transcription factor 6 p50, and C/EBP homologous protein. Interestingly, exogenous Derlin-1 resulted in a decrease in the amount of mutant SOD1, and a lesser decrease in that of wild-type SOD1, in transfected cells. Reduced SOD1 protein expression was observed in the microsomal fraction of wild-type and mutant SOD1 cells. Our results indicate that Derlin-1 regulates the turn over of SOD1 by promoting the proteasomal and autophagosomal degradation of SOD1 protein, but not by decreasing mutant SOD1 mRNA levels. Insights into the effects of Derlin-1 on mutant SOD1 may facilitate advancements in the treatment of motor neuron degeneration associated with ALS.
|
| 巻・号 |
58(3)
|
| ページ |
344-53
|
| 公開日 |
2011-2-1
|
| DOI |
10.1016/j.neuint.2010.12.010
|
| PII |
S0197-0186(10)00380-3
|
| PMID |
21185345
|
| MeSH |
Amyotrophic Lateral Sclerosis / enzymology
Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / metabolism*
Animals
Autophagy / genetics
Cell Line, Tumor
Down-Regulation / genetics
Endoplasmic Reticulum / enzymology
Endoplasmic Reticulum / metabolism*
Humans
Membrane Proteins / biosynthesis*
Membrane Proteins / genetics
Mice
Mutation / physiology
Neurons / enzymology
Neurons / metabolism*
Proteasome Endopeptidase Complex / metabolism
RNA, Messenger / biosynthesis
Stress, Physiological / genetics*
Superoxide Dismutase / antagonists & inhibitors
Superoxide Dismutase / genetics*
Superoxide Dismutase / metabolism
Superoxide Dismutase-1
|
| IF |
3.881
|
| 引用数 |
21
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
NEUROSCIENCES
|
| リソース情報 |
| ヒト・動物細胞 |
NB2a(RCB2639) |
