ArticleProceedings of the National Academy of Sciences of the United States of America2015
Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 76 citations in OpenAlex.
- Autophagy in Alzheimer's Disease: Mechanisms, Clinical Trials, and Horizons.Neuro-degenerative diseases · 2026Review
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- Modulation of Tau Protein Neurotoxic Hallmarks by Novel σChemMedChem · 2026Article
- SigmaR1 is an auxiliary translocon factor with lipid-binding activity that regulates protein and lipid droplet homeostasis.Nature communications · 2025Article
- Convenient one-pot synthesis of 1-(4-(4-(2-[RSC advances · 2025Article
- Pharmacological and Pathological Implications of Sigma-1 Receptor in Neurodegenerative Diseases.Biomedicines · 2025Review
- Mutated sigma-1R disrupts cell homeostasis in dHMN patient cells.Cellular and molecular life sciences : CMLS · 2025Article
- Integrating Network Pharmacology andCombinatorial chemistry & high throughput screening · 2025Article
- Advancements in Pharmacological Treatment of Alzheimer's Disease: The Advent of Disease-Modifying Therapies (DMTs).Brain sciences · 2024Review
- Insight into binding of endogenous neurosteroid ligands to the sigma-1 receptor.Nature communications · 2024Article
- Benzomorphan and non-benzomorphan agonists differentially alter sigma-1 receptor quaternary structure, as does types of cellular stress.Cellular and molecular life sciences : CMLS · 2024Article
- Treatment of Alzheimer's Disease: Beyond Symptomatic Therapies.International journal of molecular sciences · 2023Review
- The Sigma Receptors in Alzheimer's Disease: New Potential Targets for Diagnosis and Therapy.International journal of molecular sciences · 2023Review
- Sigma-1 receptor and seizures.Pharmacological research · 2023Review
- Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders.CNS drugs · 2023Review
- SIGMAR1 Confers Innate Resilience against Neurodegeneration.International journal of molecular sciences · 2023Review
- Sphingoid Bases Regulate the Sigma-1 Receptor-Sphingosine andInternational journal of molecular sciences · 2023Article
- Article
- Pridopidine Promotes Synaptogenesis and Reduces Spatial Memory Deficits in the Alzheimer's Disease APP/PS1 Mouse Model.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Article
- Sigma-1 Receptor in Retina: Neuroprotective Effects and Potential Mechanisms.International journal of molecular sciences · 2022Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t½, promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.
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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.