ArticleMolecular cell2017
Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease.
Article in Molecular cell, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 62 citations in OpenAlex.
- Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA.Journal of affective disorders · 2019Pooled it
- The Oral-Brain Axis: A Unified Framework Linking Trigeminal Sensorimotor Dysfunction, Chronic Stress, Neuroinflammation, and Neurodegeneration.International journal of molecular sciences · 2026Review
- Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia.Biomolecules · 2026Article
- Post-translational modifications in alzheimer's disease: proteome dynamics and emerging therapeutic strategies.Metabolic brain disease · 2026Review
- Decoding SR protein regulation: kinases, phosphatases, and therapeutic targeting strategies.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Emerging Potential of Ras-proximate-1 (Rap1) in Mediating Neurodegenerative Diseases.Current neuropharmacology · 2026Review
- Targeting SRPK3 Attenuates Cardiac Hypertrophy and Heart Failure by Improving Mitochondrial Bioenergetics through mRNA Splicing and Decay.Research (Washington, D.C.) · 2026Article
- Integrated Bioinformatics Analysis of Differentially Expressed RNA-Binding Proteins in Human Gliomas.Cellular and molecular neurobiology · 2025Article
- Phosphorylation enables progressive microtubule-associated protein proteolysis and functionalisation during neural development.bioRxiv : the preprint server for biology · 2025Article
- N-terminomics profiling of naïve and inflamed murine colon reveals proteolytic signatures of legumain.Journal of cellular physiology · 2025Article
- STAT3 ameliorates truncated tau-induced cognitive deficits.Neural regeneration research · 2024Article
- AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments.The Journal of clinical investigation · 2023Article
- FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPβ/δ-secretase in female mice.Nature communications · 2023Article
- Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders.FEBS letters · 2023Review
- C/EBPβ/AEP Signaling Drives Alzheimer's Disease Pathogenesis.Neuroscience bulletin · 2023Review
- A Review of the Recent Advances in Alzheimer's Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics.Diagnostics (Basel, Switzerland) · 2022Review
- A retrotransposon storm marks clinical phenoconversion to late-onset Alzheimer's disease.GeroScience · 2022Article
- UNC5C Receptor Proteolytic Cleavage by Active AEP Promotes Dopaminergic Neuronal Degeneration in Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Article
- Delta- and beta- secretases crosstalk amplifies the amyloidogenic pathway in Alzheimer's disease.Progress in neurobiology · 2021Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.