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P38α‐MAPK phosphorylates Snapin and reduces Snapin‐mediated BACE1 transportation in APP‐transgenic mice
Author(s) -
Schnöder Laura,
Tomic Inge,
Schwindt Laura,
Helm Dominic,
Rettel Mandy,
SchulzSchaeffer Walter,
Krause Elmar,
Rettig Jens,
Fassbender Klaus,
Liu Yang
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100017r
Subject(s) - phosphorylation , p38 mitogen activated protein kinases , microbiology and biotechnology , biology , kinase , protein kinase a , mapk/erk pathway , serine , amyloid precursor protein , transgene , biochemistry , medicine , alzheimer's disease , gene , disease
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.