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Mol Cell. 2017 Sep 7;67(5):812-825.e5. doi: 10.1016/j.molcel.2017.07.018. Epub 2017 Aug 17.

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease.

Author information

1
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2
Emory College of Arts and Sciences, Emory University, Atlanta, GA 30322, USA.
3
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Department of Translational Science and Molecular Medicine, Michigan State University, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.
5
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
6
Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Co-innovation Center of Neuroregeneration, Nantong 226001, China. Electronic address: wangjz@mails.tjmu.edu.cn.
7
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Translational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: kye@emory.edu.

Abstract

Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and tau, controlling the onset of pathogenesis of Alzheimer's disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of a phosphorylation mimetic (S226D) in young 3xTg mice strongly promotes APP and tau fragmentation and facilitates amyloid plaque deposits and neurofibrillary tangle (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreases APP and tau proteolytic cleavage, attenuates AD pathologies, and reverses cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.

KEYWORDS:

Alzheimer’s disease; post-translational regulation; protease

PMID:
28826672
PMCID:
PMC5753427
DOI:
10.1016/j.molcel.2017.07.018
[Indexed for MEDLINE]
Free PMC Article

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