RRC ID 65630
Author Schnöder L, Tomic I, Schwindt L, Helm D, Rettel M, Schulz-Schaeffer W, Krause E, Rettig J, Fassbender K, Liu Y.
Title P38α-MAPK phosphorylates Snapin and reduces Snapin-mediated BACE1 transportation in APP-transgenic mice.
Journal 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.
Volume 35(7)
Pages e21691
Published 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
Mice RBRC02192