論文 - 詳細
| RRC ID | 65630 |
|---|---|
| 著者 | Schnöder L, Tomic I, Schwindt L, Helm D, Rettel M, Schulz-Schaeffer W, Krause E, Rettig J, Fassbender K, Liu Y. |
| タイトル | P38α-MAPK phosphorylates Snapin and reduces Snapin-mediated BACE1 transportation in APP-transgenic mice. |
| ジャーナル | FASEB J |
| Abstract |
Amyloid β peptide (Aβ) is the major pathogenic molecule in Alzheimer's disease (AD). BACE1 enzyme is essential for the generation of Aβ. Deficiency of p38α-MAPK in neurons increases lysosomal degradation of BACE1 and decreases Aβ deposition in the brain of APP-transgenic mice. However, the mechanisms mediating effects of p38α-MAPK are largely unknown. In this study, we used APP-transgenic mice and cultured neurons and observed that deletion of p38α-MAPK specifically in neurons decreased phosphorylation of Snapin at serine, increased retrograde transportation of BACE1 in axons and reduced BACE1 at synaptic terminals, which suggests that p38α-MAPK deficiency promotes axonal transportation of BACE1 from its predominant locations, axonal terminals, to lysosomes in the cell body. In vitro kinase assay revealed that p38α-MAPK directly phosphorylates Snapin. By further performing mass spectrometry analysis and site-directed mutagenic experiments in SH-SY5Y cell lines, we identified serine residue 112 as a p38α-MAPK-phosphorylating site on Snapin. Replacement of serine 112 with alanine did abolish p38α-MAPK knockdown-induced reduction of BACE1 activity and protein level, and transportation to lysosomes in SH-SY5Y cells. Taken together, our study suggests that activation of p38α-MAPK phosphorylates Snapin and inhibits the retrograde transportation of BACE1 in axons, which might exaggerate amyloid pathology in AD brain. |
| 巻・号 | 35(7) |
| ページ | e21691 |
| 公開日 | 2021-7-1 |
| DOI | 10.1096/fj.202100017R |
| PMID | 34118085 |
| MeSH | Amyloid Precursor Protein Secretases / genetics Amyloid Precursor Protein Secretases / metabolism* Amyloid beta-Protein Precursor / physiology* Animals Aspartic Acid Endopeptidases / genetics Aspartic Acid Endopeptidases / metabolism* Axonal Transport Disease Models, Animal Humans Mice Mice, Transgenic Mitogen-Activated Protein Kinase 14 / genetics Mitogen-Activated Protein Kinase 14 / metabolism* Neurons / cytology Neurons / metabolism Presenilin-1 / physiology* Presynaptic Terminals / metabolism* Vesicular Transport Proteins / genetics Vesicular Transport Proteins / metabolism* |
| IF | 4.966 |
| 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 | 3 |
| 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 | |
| 実験動物マウス | RBRC02192 |