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

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单位： [a]Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China [b]Department of Pathology, Emory University, School of Medicine, Atlanta, GA, United States [c]Department of Anesthesiology, Emory University, School of Medicine, Atlanta, GA, United States [d]Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China [e]Tongji Hospital, Tongji University, School of Medicine, Shanghai, China

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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 tausplicing imbalance in tauopathies via cleaving SRPK2. © 2018 Wang et al.

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出版当年[2017]版：

大类 | 1 区

医学

小类 | 1 区免疫学 1 区医学：研究与实验

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区免疫学 1 区医学：研究与实验

第一作者：

第一作者单位： [a]Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China [b]Department of Pathology, Emory University, School of Medicine, Atlanta, GA, United States

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通讯机构： [a]Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China [b]Department of Pathology, Emory University, School of Medicine, Atlanta, GA, United States [d]Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China [e]Tongji Hospital, Tongji University, School of Medicine, Shanghai, China

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