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Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies
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 neurodege...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279401/ https://www.ncbi.nlm.nih.gov/pubmed/30373880 http://dx.doi.org/10.1084/jem.20180539 |
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author | Wang, Zhi-Hao Liu, Pai Liu, Xia Yu, Shan Ping Wang, Jian-Zhi Ye, Keqiang |
author_facet | Wang, Zhi-Hao Liu, Pai Liu, Xia Yu, Shan Ping Wang, Jian-Zhi Ye, Keqiang |
author_sort | Wang, Zhi-Hao |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6279401 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62794012019-06-03 Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies Wang, Zhi-Hao Liu, Pai Liu, Xia Yu, Shan Ping Wang, Jian-Zhi Ye, Keqiang J Exp Med Research Articles 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. Rockefeller University Press 2018-12-03 /pmc/articles/PMC6279401/ /pubmed/30373880 http://dx.doi.org/10.1084/jem.20180539 Text en © 2018 Wang et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Wang, Zhi-Hao Liu, Pai Liu, Xia Yu, Shan Ping Wang, Jian-Zhi Ye, Keqiang Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
title | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
title_full | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
title_fullStr | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
title_full_unstemmed | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
title_short | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
title_sort | delta-secretase (aep) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279401/ https://www.ncbi.nlm.nih.gov/pubmed/30373880 http://dx.doi.org/10.1084/jem.20180539 |
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