論文 - 詳細
| RRC ID | 57161 |
|---|---|
| 著者 | Valadas JS, Esposito G, Vandekerkhove D, Miskiewicz K, Deaulmerie L, Raitano S, Seibler P, Klein C, Verstreken P. |
| タイトル | ER Lipid Defects in Neuropeptidergic Neurons Impair Sleep Patterns in Parkinson's Disease. |
| ジャーナル | Neuron |
| Abstract |
Parkinson's disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts. These excessive contact sites cause abnormal lipid trafficking that depletes phosphatidylserine from the endoplasmic reticulum (ER) and disrupts the production of neuropeptide-containing vesicles. Feeding mutant animals phosphatidylserine rescues neuropeptidergic vesicle production and acutely restores normal sleep patterns in mutant animals. Hence, sleep patterns and circadian disturbances in Parkinson's disease models are explained by excessive ER-mitochondrial contacts, and blocking their formation or increasing phosphatidylserine levels rescues the defects in vivo. |
| 巻・号 | 98(6) |
| ページ | 1155-1169.e6 |
| 公開日 | 2018-6-27 |
| DOI | 10.1016/j.neuron.2018.05.022 |
| PII | S0896-6273(18)30420-3 |
| PMID | 29887339 |
| MeSH | Animals Disease Models, Animal Drosophila Proteins / genetics Drosophila melanogaster Endoplasmic Reticulum / drug effects Endoplasmic Reticulum / metabolism* Humans Hypothalamus / metabolism* Induced Pluripotent Stem Cells Lipid Metabolism* Mitochondria / metabolism Neurons / metabolism* Neuropeptides / metabolism Parkinson Disease / genetics Parkinson Disease / metabolism Parkinson Disease / physiopathology* Phosphatidylserines / metabolism* Phosphatidylserines / pharmacology Protein Serine-Threonine Kinases / genetics Sleep* / drug effects Sleep Disorders, Circadian Rhythm / genetics Sleep Disorders, Circadian Rhythm / metabolism Sleep Disorders, Circadian Rhythm / physiopathology* Ubiquitin-Protein Ligases / genetics Ubiquitination |
| IF | 14.403 |
| 引用数 | 19 |
| 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 | 54 |
| 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 | |
| ショウジョウバエ | |