ArticleMolecular psychiatry2022
Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling.
Article in Molecular psychiatry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 33 citations in OpenAlex.
- Synaptic proteomics identifies cathepsin B as a regulator of synapse remodelling during learning.bioRxiv : the preprint server for biology · 2026Article
- Phosphatase and tensin homolog: A potential target for therapeutic intervention in optic nerve regeneration.Neural regeneration research · 2026Article
- CYLD-mediated lysine63 deubiquitination regulates synaptic transmission and autophagy to mitigate age-related sequelae.Nature communications · 2026Article
- Zhi-Zi-Chi Decoction Alleviates Depressive-like Behaviors by Regulating Gut Microbiota and Targeting the AMPK/PI3K-TOR Pathway via Its Metabolite Protocatechuic Acid.Pharmaceuticals (Basel, Switzerland) · 2026Article
- PPARγ as a predictive biomarker for antidepressant response in major depressive disorder: Insights from TNIP1 transcriptional regulation.Brain, behavior, & immunity - health · 2026Article
- Decoding autophagy in neuro-tumor crosstalk: from underlying mechanisms to translational opportunities.Theranostics · 2026Review
- Downhill running induced mitophagy in rat soleus muscle via the AMPK pathway.Journal of physiology and biochemistry · 2025Article
- Interaction of metabolic and inflammatory dysregulation on central degeneration and cognitive function in behavioral variant Frontotemporal dementia.Journal of neurology · 2025Article
- AKT and DUBs: a bidirectional relationship.Cellular & molecular biology letters · 2025Review
- Role of CYLD in brain physiology and pathology.Journal of molecular medicine (Berlin, Germany) · 2025Review
- Article
- Constitutive expression of the deubiquitinating enzyme CYLD does not affect microglia phenotype or function in homeostasis and neuroinflammation.Journal of molecular medicine (Berlin, Germany) · 2024Article
- Targeting Nr2e3 to Modulate Tet2 Expression: Therapeutic Potential for Depression Treatment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Case report: Multiple facial trichoepitheliomas caused by p.Val835SerfsTer52 variant ofFrontiers in medicine · 2024Article
- Candidate Genes for IgA Nephropathy in Pediatric Patients: Exome-Wide Association Study.International journal of molecular sciences · 2023Article
- Inactivation of Tumor Suppressor CYLD Inhibits Fibroblast Reprogramming to Pluripotency.Cancers · 2023Article
- CYLD in health and disease.Disease models & mechanisms · 2023Review
- Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.Biomedicines · 2023Review
- Biocytin-Labeling in Whole-Cell Recording: Electrophysiological and Morphological Properties of Pyramidal Neurons in CYLD-Deficient Mice.Molecules (Basel, Switzerland) · 2023Article
- Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence.Stem cell research & therapy · 2023Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation, and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux, and conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.
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