| First Author | Schnöder L | Year | 2021 |
| Journal | FASEB J | Volume | 35 |
| Issue | 7 | Pages | e21691 |
| PubMed ID | 34118085 | Mgi Jnum | J:310781 |
| Mgi Id | MGI:6754194 | Doi | 10.1096/fj.202100017R |
| Citation | Schnoder L, et al. (2021) P38alpha-MAPK phosphorylates Snapin and reduces Snapin-mediated BACE1 transportation in APP-transgenic mice. FASEB J 35(7):e21691 |
| abstractText | Amyloid beta peptide (Abeta) is the major pathogenic molecule in Alzheimer's disease (AD). BACE1 enzyme is essential for the generation of Abeta. Deficiency of p38alpha-MAPK in neurons increases lysosomal degradation of BACE1 and decreases Abeta deposition in the brain of APP-transgenic mice. However, the mechanisms mediating effects of p38alpha-MAPK are largely unknown. In this study, we used APP-transgenic mice and cultured neurons and observed that deletion of p38alpha-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 p38alpha-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 p38alpha-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 p38alpha-MAPK-phosphorylating site on Snapin. Replacement of serine 112 with alanine did abolish p38alpha-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 p38alpha-MAPK phosphorylates Snapin and inhibits the retrograde transportation of BACE1 in axons, which might exaggerate amyloid pathology in AD brain. |
