論文 - 詳細
| RRC ID | 57548 |
|---|---|
| 著者 | Hui KK, Takashima N, Watanabe A, Chater TE, Matsukawa H, Nekooki-Machida Y, Nilsson P, Endo R, Goda Y, Saido TC, Yoshikawa T, Tanaka M. |
| タイトル | GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior. |
| ジャーナル | Sci Adv |
| Abstract |
Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted Atg7 in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to Atg7 deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2) to differentially form high-molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABAA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation. |
| 巻・号 | 5(4) |
| ページ | eaau8237 |
| 公開日 | 2019-4-1 |
| DOI | 10.1126/sciadv.aau8237 |
| PII | aau8237 |
| PMID | 30989111 |
| PMC | PMC6457945 |
| MeSH | Animals Apoptosis Regulatory Proteins / metabolism* Autophagy* Brain / pathology* Humans Interneurons / metabolism Mice Mice, Transgenic Microtubule-Associated Proteins / metabolism* Neurons / metabolism Prosencephalon / physiology Protein Aggregates Protein Binding Protein Transport Receptors, GABA-A / metabolism* Social Behavior* |
| IF | 12.804 |
| 引用数 | 8 |
| 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 | 24 |
| 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 | CSII-CMV-MCS-IRES2-Venus (RDB04383) pCAG-HIVgp (RDB04394) |