ArticleThe Journal of clinical investigation2019
TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 2 of them syntheses that pooled it.
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Who cites it
37 citing papers in PubMed, 2 syntheses or guidelines pooled it, 61 citations in OpenAlex.
- Medications on hypertension, hyperlipidemia, diabetes, and risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2022 · on this mapPooled it
- Diabetes Mellitus and Amyotrophic Lateral Sclerosis: A Systematic Review.Biomolecules · 2021Pooled it
- Blood Glucose Homeostasis is Preserved in Patients with Mild-to-moderate Spinocerebellar Ataxia Type 2.Cerebellum (London, England) · 2026Article
- Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.JCI insight · 2026Article
- AAV Vector-Mediated Modulation of Signaling Pathways in Neurological Disorders: Insights From Cellular, Animal, and Human Studies.Cell biochemistry and function · 2026Review
- Polyadenylation of insulin mRNA by Tent5a regulates pancreatic beta cells.Nature communications · 2026Article
- Neuronal TDP-43 regulates myelin formation via neurexin 1 mRNA stabilization.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Type 2 diabetes mellitus, antidiabetics, and the risk of amyotrophic lateral sclerosis.Amyotrophic lateral sclerosis & frontotemporal degeneration · 2025Article
- TDP-43: unveiling the hidden key to cellular fate decisions.Cell communication and signaling : CCS · 2025Review
- Exploring the Role of Diabetes in ALS: A Population-Based Cohort Study.Life (Basel, Switzerland) · 2025Article
- Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.Nature neuroscience · 2025Article
- Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects.Science advances · 2025Article
- Article
- Nutritional and Microbiota-Based Approaches in Amyotrophic Lateral Sclerosis: From Prevention to Treatment.Nutrients · 2024Review
- Alcohol consumers with liver pathology rarely display α-synuclein pathology.Acta neuropathologica · 2024Article
- Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2024Article
- IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation.The Journal of cell biology · 2024Article
- Identification and validation of diagnostic genes associated with neutrophil extracellular traps of type 2 diabetes mellitus.Frontiers in genetics · 2024Article
- Targeted inCITE-Seq Analysis Identifies the Loss of Nuclear TDP-43 in Endothelium as a Mediator of Blood Brain Barrier Signaling Pathway Dysfunction in Neurodegeneration.bioRxiv : the preprint server for biology · 2023Article
- Diabetes: a tipping point in neurodegenerative diseases.Trends in molecular medicine · 2023Review
Corrections and comments
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Authors and funding
28 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.
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