Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease
Document Type
Article
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
Publication Date
9-7-2017
Publication Title
Molecular Cell
ISSN
10972765
E-ISSN
10974164
Volume
67
Issue
5
First Page
812
Last Page
825.e5
PubMed ID
28826672
Digital Object Identifier (DOI)
10.1016/j.molcel.2017.07.018
Recommended Citation
Wang, Zhi Hao; Liu, Pai; Liu, Xia; Manfredsson, Fredric P.; Sandoval, Ivette M.; Yu, Shan Ping; Wang, Jian Zhi; and Ye, Keqiang, "Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease" (2017). Translational Neuroscience. 1412.
https://scholar.barrowneuro.org/neurobiology/1412