ArticleThe Journal of biological chemistry2019
Spleen tyrosine kinase (SYK) blocks autophagic Tau degradation
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
- Identifying transcriptomic signatures that mediate the causal effect of genotype on Alzheimer's disease.Frontiers in neuroscience · 2026Article
- Development of a time-resolved fluorescence resonance energy transfer ultra-high throughput screening assay targeting SYK and FCER1G interaction.SLAS discovery : advancing life sciences R & D · 2024Article
- Development of a Time-Resolved Fluorescence Resonance Energy Transfer ultra-high throughput screening assay for targeting SYK and FCER1G interaction.bioRxiv : the preprint server for biology · 2024Article
- Autophagy in Neuroinflammation: A Focus on Epigenetic Regulation.Aging and disease · 2024Review
- A Spleen Tyrosine Kinase's Sky in Neuronal Degeneration.Neuroscience bulletin · 2024Article
- Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.PloS one · 2024Article
- Blockade of Syk modulates neutrophil immune-responses via the mTOR/RUBCNL-dependent autophagy pathway to alleviate intestinal inflammation in ulcerative colitis.Precision clinical medicine · 2023Article
- Syk regulates the haemocyte autophagy through inducing the mRNA expressions of autophagy-related genes and the cleavage ofFish and shellfish immunology reports · 2023Article
- Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.bioRxiv : the preprint server for biology · 2023Article
- Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer's disease? From preclinical studies to the clinical trials.Molecular psychiatry · 2023Review
- Syk inhibitors protect against microglia-mediated neuronal loss in culture.Frontiers in aging neuroscience · 2023Article
- Identification of Novel Kinases of Tau Using Fluorescence Complementation Mass Spectrometry (FCMS).Molecular & cellular proteomics : MCP · 2022Article
- Lipopolysaccharide-Induced Model of Neuroinflammation: Mechanisms of Action, Research Application and Future Directions for Its Use.Molecules (Basel, Switzerland) · 2022Review
- Article
- The Role of Alpha-Synuclein Autoantibodies in the Induction of Brain Inflammation and Neurodegeneration in Aged Humans.Frontiers in aging neuroscience · 2022Article
- Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology.Alzheimer's & dementia (New York, N. Y.) · 2022Article
- Tau Protein Interaction Partners and Their Roles in Alzheimer's Disease and Other Tauopathies.International journal of molecular sciences · 2021Review
- Artificial intelligence-based computational framework for drug-target prioritization and inference of novel repositionable drugs for Alzheimer's disease.Alzheimer's research & therapy · 2021Article
- Modulatory Effects of Autophagy on APP Processing as a Potential Treatment Target for Alzheimer's Disease.Biomedicines · 2020Review
- Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI.Acta neuropathologica communications · 2020Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Spleen tyrosine kinase (SYK) plays a major role in inflammation and in adaptive immune responses and could therefore contribute to the neuroinflammation observed in various neurodegenerative diseases. Indeed, previously we have reported that SYK also regulates β-amyloid (Aβ) production and hyperphosphorylation of Tau protein involved in these diseases. Moreover, SYK hyperactivation occurs in a subset of activated microglia, in dystrophic neurites surrounding Aβ deposits, and in neurons affected by Tau pathology both in individuals with Alzheimer's disease (AD) and in AD mouse models. SYK activation increases Tau phosphorylation and accumulation, suggesting that SYK could be an attractive target for treating AD. However, the mechanism by which SYK affects Tau pathology is not clear. In this study, using cell biology and biochemical approaches, along with immunoprecipitation and immunoblotting, quantitative RT-PCR, and ELISAs, we found that SYK inhibition increases autophagic Tau degradation without impacting Tau production. Using neuron-like SH-SY5Y cells, we demonstrate that SYK acts upstream of the mammalian target of rapamycin (mTOR) pathway and that pharmacological inhibition or knockdown of SYK decreases mTOR pathway activation and increases autophagic Tau degradation. Interestingly, chronic SYK inhibition in a tauopathy mouse model profoundly reduced Tau accumulation, neuroinflammation, neuronal and synaptic loss, and also reversed defective autophagy. Our results further suggest that the SYK up-regulation observed in the brains of individuals with AD contributes to defective autophagic clearance leading to the accumulation of pathogenic Tau species. These findings further highlight SYK as a therapeutic target for the treatment of tauopathies and other neurodegenerative proteinopathies associated with defective autophagic clearance.
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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.