ArticleProceedings of the National Academy of Sciences of the United States of America2014
Calcineurin determines toxic versus beneficial responses to α-synuclein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed, 133 citations in OpenAlex.
- Microglia respond to and induce anxiety and grooming in mice using calcium signaling.Molecular psychiatry · 2026Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Calcium overload induced mitochondrial and lysosomal dysfunction is regulated by Tousled-like kinase in a-synucleinopathy.Cell death & disease · 2026Article
- One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Loss of CAMKK2 and iron-transport proteins-transferrin and its receptor-in the Alzheimer's disease hippocampus: link to tau pathology.Frontiers in cell and developmental biology · 2026Article
- Evaluating the Neuroprotective and Acetylcholinesterase Inhibitory Properties of Four Calcineurin Inhibitor Drugs: Tacrolimus, Pimecrolimus, Cyclosporin A, and Voclosporin.Molecular neurobiology · 2025Article
- Inhibition of astrocyte signaling leads to sex-specific changes in microglia phenotypes in a diet-based model of cerebral small vessel disease.Journal of neuroinflammation · 2025Article
- Role of Cellular Senescence in Parkinson's Disease: Potential for Disease-Modification Through Senotherapy.Biomedicines · 2025Review
- Trace amine-associated receptor 1 (TAAR1): an emerging therapeutic target for neurodegenerative, neurodevelopmental, and neurotraumatic disorders.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Calcineurin-mediated regulation of growth-associated protein 43 is essential for neurite and synapse formation and protects against α-synuclein-induced degeneration.Frontiers in aging neuroscience · 2025Article
- Review
- Calcium influx: An essential process by which α-Synuclein regulates morphology of erythrocytes.Journal of advanced research · 2024Article
- Development of a monoclonal antibody specific for a calpain-generated ∆48 kDa calcineurin fragment, a marker of distressed astrocytes.Journal of neuroscience methods · 2024Article
- Advancements in Genetic and Biochemical Insights: Unraveling the Etiopathogenesis of Neurodegeneration in Parkinson's Disease.Biomolecules · 2024Review
- Reduced Prevalence of Parkinson's Disease in Patients Prescribed Calcineurin Inhibitors.Journal of Parkinson's disease · 2024Article
- Calcineurin stimulation by Cnb1p overproduction mitigates protein aggregation and α-synuclein toxicity in a yeast model of synucleinopathy.Cell communication and signaling : CCS · 2023Article
- The alpha-synuclein oligomers activate nuclear factor of activated T-cell (NFAT) modulating synaptic homeostasis and apoptosis.Molecular medicine (Cambridge, Mass.) · 2023Article
- Tripartite Motif Protein Family in Central Nervous System Diseases.Cellular and molecular neurobiology · 2023Review
- Calcineurin inhibition protects against dopamine toxicity and attenuates behavioral decline in a Parkinson's disease model.Cell & bioscience · 2023Article
- Revisiting the critical roles of reactive astrocytes in neurodegeneration.Molecular psychiatry · 2023Review
27 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 8 institutions in 2 countries.
Funding
Abstract
Calcineurin (CN) is a highly conserved Ca(2+)-calmodulin (CaM)-dependent phosphatase that senses Ca(2+) concentrations and transduces that information into cellular responses. Ca(2+) homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca(2+), thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN's spectrum of substrates toward protective pathways. Modulating CN or CN's substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase's activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.
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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.