ArticleExperimental & molecular medicine2022
TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis.
Article in Experimental & molecular medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 79 citations in OpenAlex.
- The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.Nature neuroscience · 2026Article
- Epigenetic dynamics of cellular senescence: From mechanistic insights to precision senotherapy.Chinese medical journal · 2026Review
- Unraveling Lysosomal Exocytosis: From Molecular Mechanisms to Physiological Functions.Traffic (Copenhagen, Denmark) · 2026Review
- Do microplastics play a role in the pathogenesis of neurodegenerative diseases? Shared pathophysiological pathways for Alzheimer's and Parkinson's disease.Molecular and cellular biochemistry · 2026Review
- Targeting cellular senescence through nutritional senotherapeutics in brain aging and neurodegenerative diseases.Frontiers in nutrition · 2026Review
- GPNMB is a biomarker for lysosomal dysfunction and is secreted via LRRK2-modulated lysosomal exocytosis.Science advances · 2025Article
- Effects of disease severity-based nursing intervention on immune function and IFN-γ, IL-6, and TNF-α for children with IgA vasculitis nephritis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Nortriptyline Inhibits Lysosomal Exocytosis-Mediated SASP During Gastric Cancer Progression via Targeting HOXA1-PITX2 Phase Separation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Aggregation and Propagation of α-Synuclein in Parkinson's Disease: A Bibliometric Perspective.Brain and behavior · 2025Article
- Artemis (DCLRE1C) Acts as a Target to Enhance Radiotherapy Response in Triple-Negative Breast Cancer.Cancers · 2025Article
- Elevated hexosylceramides in Parkinson's disease cause gene upregulations in neurons mimicking responses to pathogens.NPJ Parkinson's disease · 2025Article
- The Emerging Role of the Molecular Chaperone Clusterin in Parkinson's Disease.International journal of molecular sciences · 2025Review
- Role of Cellular Senescence in Parkinson's Disease: Potential for Disease-Modification Through Senotherapy.Biomedicines · 2025Review
- Taurine Alleviates Pancreatic β-Cell Senescence by Inhibition of p53 Pathway.Journal of diabetes · 2025Article
- A hypothesis explaining Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies overlap.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- The impact of different dietary flavonoids on the risk of coronary heart disease in cancer patients and that on the prognosis of patients with cancer and coronary heart disease.European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) · 2025Article
- Microglia-driven inflammation induces progressive tauopathies and synucleinopathies.Experimental & molecular medicine · 2025Article
- Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.Aging and disease · 2025Review
- A Sensitive and Versatile Cell-Based Assay Combines Luminescence and Trapping Approaches to Monitor Unconventional Protein Secretion.Traffic (Copenhagen, Denmark) · 2025Article
- Senescent brain cell types in Alzheimer's disease: Pathological mechanisms and therapeutic opportunities.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
Corrections and comments
- Erratum issued
Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinson's disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of aggregates remains unknown. Here, using in vitro cultures, we found that soluble factors secreted from activated microglia promote cell-to-cell propagation of α-synuclein and further showed that among these soluble factors, TNF-α had the most robust stimulatory activity. Treatment of neurons with TNF-α triggered cellular senescence, as shown by transcriptomic analyses demonstrating induction of senescence-associated genes and immunoanalysis of senescence phenotype marker proteins. Interestingly, secretion of α-synuclein was increased in senescent neurons, reflecting acquisition of a senescence-associated secretory phenotype (SASP). Using vacuolin-1, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Correlative light and electron microscopy and immunoelectron microscopy confirmed that propagating α-synuclein aggregates were present in electron-dense lysosome-like compartments. TNF-α promoted the SASP through stimulation of lysosomal exocytosis, thereby increasing the secretion of α-synuclein. Collectively, these results suggest that TNF-α is the major inflammatory factor that drives cell-to-cell propagation of α-synuclein by promoting the SASP and subsequent secretion of α-synuclein.
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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.