ArticleAutophagy2023
Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine.
Article in Autophagy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 56 citations in OpenAlex.
- Neuromodulatory roles of the sigma-1 receptor in behavior and drug sensitization during development.Acta pharmacologica Sinica · 2026Article
- Hyperoside protects against poly-GR-mediated neurodegeneration via regulation of mitochondrial fission and oxidative stress in C9orf72-associated ALS.Chinese medicine · 2026Article
- Targeting Neuroinflammation in Depression: The Integrative Role of Sigma-1 Receptor Modulation.Journal of neurochemistry · 2026Review
- The Role of Sigmar1 in Autophagy Regulation and Disease Therapy.International journal of molecular sciences · 2026Review
- Poly-GR promotes ferroptosis-associated vulnerability in C9orf72-ALS.Cell & bioscience · 2026Article
- Autophagy: From Molecular Mechanisms to Disease Regulation and Therapeutic Strategies.Current issues in molecular biology · 2026Review
- Identifying Key Epigenetic Modification-Related Genes for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma and Cellular Validation.Current gene therapy · 2026Article
- Pridopidine, a Potent and Selective Therapeutic Sigma-1 Receptor (S1R) Agonist for Treating Neurodegenerative Diseases.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Lithium exposure causes ferroptosis to induce unexplained miscarriage through non-canonical MBOAT1 pathway.Nature communications · 2025Article
- Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.Molecular neurobiology · 2025Article
- MoSec13 combined with MoGcn5b modulates MoAtg8 acetylation and regulates autophagy inAutophagy · 2025Article
- Lithium Exposure Causes Trophoblast Cuproptosis by Upregulating FOXO1/STEAP4 Axis in Unexplained Miscarriage.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Targeting the sigma-1 receptor with pridopidine induces functional neurorestoration in spinal cord ischemia-reperfusion injury.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Repurposing Sigma-1 Receptor-Targeting Drugs for Therapeutic Advances in Neurodegenerative Disorders.Pharmaceuticals (Basel, Switzerland) · 2025Review
- The Safety Profile of Pridopidine, a Novel Sigma-1 Receptor Agonist for the Treatment of Huntington's Disease.CNS drugs · 2025Article
- Sigma-1 Receptor Specific Biological Functions, Protective Role, and Therapeutic Potential in Cardiovascular Diseases.Cardiovascular toxicology · 2025Review
- Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- The sigma-1 receptor as a neurohomeostatic decision hub for GABARAP-mediated receptor trafficking and macroautophagy.Frontiers in molecular biosciences · 2025Article
- Nuclear pore dysfunction and disease: a complex opportunity.Nucleus (Austin, Tex.) · 2024Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 5 countries.
Funding
Abstract
Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importinβ1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also as a chaperone-operated signaling molecule enabling TFEB-mediated autophagy. Our data suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired.
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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.