P38α-MAPK phosphorylates Snapin and reduces Snapin-mediated BACE1 transportation in APP-transgenic mice.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Laura SchnöderYang Liu

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,...Continue Reading

References

May 1, 1975·Proceedings of the National Academy of Sciences of the United States of America·M D WeingartenM W Kirschner
Dec 1, 1986·The Journal of Cell Biology·D G Drubin, M W Kirschner
Oct 28, 1998·Nature·M J BerridgeP Lipp
Apr 27, 1999·Journal of Neurochemistry·K HensleyG Bing
Jun 20, 2000·Neurobiology of Aging·H AkiyamaT Wyss-Coray
Nov 18, 2000·Journal of Neuropathology and Experimental Neurology·X ZhuM A Smith
Jun 7, 2001·Proceedings of the National Academy of Sciences of the United States of America·A AlonsoK Iqbal
Apr 12, 2002·Journal of Neurochemistry·Ursula BodendorfPaolo Paganetti
May 9, 2003·The Journal of Biological Chemistry·Stephen H PasternakDon J Mahuran
Jun 11, 2004·The Journal of Biological Chemistry·Alejandra del C AlonsoKhalid Iqbal
Aug 4, 2004·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hong QingWeihong Song
Nov 11, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jin-Hua TianZu-Hang Sheng
Jul 16, 2008·Journal of Proteome Research·Jian WangFuchu He
Oct 18, 2008·Nature Protocols·Peter R DunkleyPhillip J Robinson
May 27, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sooyeon LeeRalph A Nixon
Jul 5, 2012·Cold Spring Harbor Perspectives in Medicine·Lennart Mucke, Dennis J Selkoe
May 16, 2013·Neurobiology of Aging·Kan XieKlaus Fassbender
Aug 21, 2013·Experimental & Molecular Medicine·Hye Jin YunWongi Seol
Jan 7, 2014·Molecular Neurodegeneration·Virginie Buggia-PrévotGopal Thinakaran
Oct 4, 2014·Science·Mikhail M SavitskiGerard Drewes
Jan 17, 2015·EMBO Molecular Medicine·Yasuhiko KizukaNaoyuki Taniguchi
Mar 22, 2015·Human Molecular Genetics·Malte ButzlaffAaron Voigt
Dec 29, 2016·The Journal of Biological Chemistry·Tuancheng FengQian Cai
Feb 6, 2017·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Xuan YeQian Cai
Dec 21, 2017·Brain Structure & Function·Yann DeckerKlaus Fassbender
Nov 11, 2019·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Qiu T RuanCamron D Bryant
Jun 1, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Laura SchnöderYang Liu

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alzheimer's Disease: Endosomes

Dysfunctional endosomal trafficking may be associated with Alzheimer’s disease (AD) pathology. Targeting the endosome may advance treatment options for AD. Here is the latest research on endosomes and AD.

Alzheimer's Disease: Animal Models

Alzheimer's disease is a neurodegenerative disease which can be studied using various experimental systems. This feed focuses on animal models used for Alzheimer's disease research.

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.