論文 - 詳細
| RRC ID | 51527 |
|---|---|
| 著者 | Cooper JF, Machiela E, Dues DJ, Spielbauer KK, Senchuk MM, Van Raamsdonk JM. |
| タイトル | Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson's disease models. |
| ジャーナル | Sci Rep |
| Abstract |
While the pathogenesis of Parkinson's disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.1/DJ-1). We found that pdr-1 and pink-1 mutants exhibit deficits in dopamine-dependent behaviors, but no loss of dopamine neurons, while djr-1.1 mutants showed an increased sensitivity to oxidative stress. In examining mitochondrial morphology and function, we found that djr-1.1 mutants exhibit increased mitochondrial fragmentation leading to decreased rate of oxidative phosphorylation and ATP levels. pdr-1 and pink-1 mutants show an accumulation of dysfunctional mitochondria with age, which leads to activation of the mitochondrial unfolded protein response (mitoUPR). Preventing the upregulation of the mitoUPR with a deletion in atfs-1 results in decreased lifespan and dopamine neuronal loss in pdr-1 and pink-1 mutants but not in wild-type worms. Overall, our results suggest that mutations in pdr-1 and pink-1 cause the accumulation of dysfunctional mitochondria, which activates the mitoUPR to mitigate the detrimental effect of these mutations on dopamine neuron survival. |
| 巻・号 | 7(1) |
| ページ | 16441 |
| 公開日 | 2017-11-27 |
| DOI | 10.1038/s41598-017-16637-2 |
| PII | 10.1038/s41598-017-16637-2 |
| PMID | 29180793 |
| PMC | PMC5703891 |
| MeSH | Animals Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cell Death / drug effects Cell Survival / drug effects Disease Models, Animal Dopamine / pharmacology Dopaminergic Neurons / drug effects Dopaminergic Neurons / metabolism Dopaminergic Neurons / pathology* Green Fluorescent Proteins / metabolism Longevity* / drug effects Mitochondria / drug effects Mitochondria / metabolism* Mutation / genetics Nerve Degeneration / metabolism Nerve Degeneration / pathology Oxidative Stress / drug effects Parkinson Disease / pathology* Unfolded Protein Response* / drug effects |
| IF | 3.998 |
| 引用数 | 22 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 9 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm1346 tm918 |