Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies
Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K.
Rockefeller University Press
Published 2018
Rockefeller University Press
Published 2018
| Publication Date: |
2018-12-04
|
|---|---|
| Publisher: |
Rockefeller University Press
|
| Print ISSN: |
0022-1007
|
| Electronic ISSN: |
1540-9538
|
| Topics: |
Medicine
|
| Keywords: |
Neuroscience
|
| Published by: |
| _version_ | 1836399096459427842 |
|---|---|
| autor | Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. |
| beschreibung | 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. |
| citation_standardnr | 6364244 |
| datenlieferant | ipn_articles |
| feed_id | 96 |
| feed_publisher | Rockefeller University Press |
| feed_publisher_url | http://www.rupress.org/ |
| insertion_date | 2018-12-04 |
| journaleissn | 1540-9538 |
| journalissn | 0022-1007 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | Rockefeller University Press |
| quelle | Journal of Experimental Medicine |
| relation | http://jem.rupress.org/cgi/content/short/215/12/3038?rss=1 |
| schlagwort | Neuroscience |
| search_space | articles |
| shingle_author_1 | Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. |
| shingle_author_2 | Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. |
| shingle_author_3 | Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. |
| shingle_author_4 | Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. |
| shingle_catch_all_1 | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies Neuroscience 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. Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. Rockefeller University Press 0022-1007 00221007 1540-9538 15409538 |
| shingle_catch_all_2 | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies Neuroscience 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. Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. Rockefeller University Press 0022-1007 00221007 1540-9538 15409538 |
| shingle_catch_all_3 | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies Neuroscience 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. Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. Rockefeller University Press 0022-1007 00221007 1540-9538 15409538 |
| shingle_catch_all_4 | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies Neuroscience 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. Wang, Z.-H., Liu, P., Liu, X., Yu, S. P., Wang, J.-Z., Ye, K. Rockefeller University Press 0022-1007 00221007 1540-9538 15409538 |
| shingle_title_1 | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
| shingle_title_2 | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
| shingle_title_3 | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
| shingle_title_4 | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
| timestamp | 2025-06-30T23:37:32.640Z |
| titel | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
| titel_suche | Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies |
| topic | WW-YZ |
| uid | ipn_articles_6364244 |