ArticleActa neuropathologica2016
The phosphatase calcineurin regulates pathological TDP-43 phosphorylation.
Article in Acta neuropathologica, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 55 citations in OpenAlex.
- Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts.Acta neuropathologica · 2026Article
- Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.BMC medicine · 2026Review
- Molecular Modulation of the Crosstalk Between TDP-43 and SOD1.International journal of molecular sciences · 2026Article
- Review
- Calcineurin depletion coincides with phosphorylated TDP-43 deposition in a mouse model of ALS/FTLD-TDP.Acta neuropathologica communications · 2026Article
- TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.The FEBS journal · 2026Review
- One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration.Molecular neurodegeneration · 2025Review
- TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm.Communications biology · 2025Article
- Towards Understanding Neurodegenerative Diseases: Insights fromInternational journal of molecular sciences · 2023Review
- Looking for answers far away from the soma-the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS.Molecular neurodegeneration · 2023Review
- Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function.Science advances · 2023Article
- Simple models to understand complex disease: 10 years of progress fromFrontiers in neuroscience · 2023Review
- Mechanisms underlying TDP-43 pathology and neurodegeneration: An updated Mini-Review.Frontiers in aging neuroscience · 2023Review
- Identification of TARDBP Gly298Ser as a founder mutation for amyotrophic lateral sclerosis in Southern China.BMC medical genomics · 2022Article
- TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans.Disease models & mechanisms · 2022Article
- Regulation of TDP-43 phosphorylation in aging and disease.GeroScience · 2021Article
- Antifungal activity of dendritic cell lysosomal proteins against Cryptococcus neoformans.Scientific reports · 2021Article
- Review
- Modeling neurodegeneration inDisease models & mechanisms · 2020Review
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90 % of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date, several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together, these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.
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