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J Exp Med. 2018 Dec 3;215(12):3038-3056. doi: 10.1084/jem.20180539. Epub 2018 Oct 29.

Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies.

Wang ZH1,2, Liu P2, Liu X2, Yu SP3, Wang JZ4,5, Ye K6,7.

Author information

1
Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
3
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA.
4
Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China wangjz@mails.tjmu.edu.cn.
5
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
6
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA kye@emory.edu.
7
Tongji Hospital, Tongji University School of Medicine, Shanghai, China.

Abstract

SRPK2 is abnormally activated in tauopathies including Alzheimer's disease (AD). SRPK2 is known to play an important role in pre-mRNA splicing by phosphorylating SR-splicing factors. Dysregulation of tau exon 10 pre-mRNA splicing causes pathological imbalances in 3R- and 4R-tau, leading to neurodegeneration; however, the role of SRPK2 in these processes remains unclear. Here we show that delta-secretase (also known as asparagine endopeptidase; AEP), which is activated in AD, cleaves SRPK2 and increases its nuclear translocation as well as kinase activity, augmenting exon 10 inclusion. Conversely, AEP-uncleavable SRPK2 N342A mutant increases exon 10 exclusion. Lentiviral expression of truncated SRPK2 increases 4R-tau isoforms and accelerates cognitive decline in htau mice. Uncleavable SRPK2 N342A expression improves synaptic functions and prevents spatial memory deficits in tau intronic mutant FTDP-17 transgenic mice. Hence, AEP mediates tau-splicing imbalance in tauopathies via cleaving SRPK2.

PMID:
30373880
PMCID:
PMC6279401
DOI:
10.1084/jem.20180539
[Indexed for MEDLINE]
Free PMC Article

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