論文 - 詳細
| RRC ID | 36033 |
|---|---|
| 著者 | Reddy K, Cusack CL, Nnah IC, Khayati K, Saqcena C, Huynh TB, Noggle SA, Ballabio A, Dobrowolski R. |
| タイトル | Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency. |
| ジャーナル | Cell Rep |
| Abstract |
Attenuated auto-lysosomal system has been associated with Alzheimer disease (AD), yet all underlying molecular mechanisms leading to this impairment are unknown. We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1) is dysregulated in cells deficient in presenilin, a protein associated with AD. In these cells, mTORC1 is constitutively tethered to lysosomal membranes, unresponsive to starvation, and inhibitory to TFEB-mediated clearance due to a reduction in Sestrin2 expression. Normalization of Sestrin2 levels through overexpression or elevation of nuclear calcium rescued mTORC1 tethering and initiated clearance. While CLEAR network attenuation in vivo results in buildup of amyloid, phospho-Tau, and neurodegeneration, presenilin-knockout fibroblasts and iPSC-derived AD human neurons fail to effectively initiate autophagy. These results propose an altered mechanism for nutrient sensing in presenilin deficiency and underline an importance of clearance pathways in the onset of AD. |
| 巻・号 | 14(9) |
| ページ | 2166-2179 |
| 公開日 | 2016-3-8 |
| DOI | 10.1016/j.celrep.2016.02.006 |
| PII | S2211-1247(16)30074-2 |
| PMID | 26923592 |
| PMC | PMC4793148 |
| MeSH | Alzheimer Disease / metabolism Amino Acids / metabolism Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism Brain / metabolism Brain / pathology Calcium / metabolism Cell Nucleus / metabolism Cells, Cultured Gene Regulatory Networks Humans Mechanistic Target of Rapamycin Complex 1 Mice Mice, Knockout Multiprotein Complexes / metabolism Nuclear Proteins / metabolism Nutritional Physiological Phenomena Peroxidases Presenilins / genetics* Presenilins / metabolism TOR Serine-Threonine Kinases / metabolism |
| IF | 8.109 |
| 引用数 | 42 |
| WOS 分野 | CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 13 |
| 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 | |
| 遺伝子材料 | pGL4-phSESN2 (RDB07413) |