Please use this identifier to cite or link to this item: doi:10.22028/D291-34615
Title: 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
Schulz-Schaeffer, Walter
Krause, Elmar
Rettig, Jens
Fassbender, Klaus
Liu, Yang
Language: English
Title: The FASEB Journal
Volume: 35
Issue: 7
Publisher/Platform: Wiley
Year of Publication: 2021
Free key words: Alzheimer's disease
DDC notations: 610 Medicine and health
Publikation type: Journal Article
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.
DOI of the first publication: 10.1096/fj.202100017R
Link to this record: urn:nbn:de:bsz:291--ds-346155
ISSN: 1530-6860
Date of registration: 2-Sep-2021
Faculty: M - Medizinische Fakultät
Department: M - Neurologie und Psychiatrie
M - Neuropathologie
M - Physiologie
Professorship: M - Prof. Dr. Klaus Faßbender
M - Prof. Dr. Jens Rettig
M - Prof. Dr. Walter Schulz-Schaeffer
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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