ArticlePLoS biology2020
LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient.
Article in PLoS biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Investigational eIF2B activator DNL343 modulates the integrated stress response in preclinical models of TDP-43 pathology and individuals with ALS in a randomized clinical trial.Nature communications · 2025Trial
- Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease.The protein journal · 2025Review
- LSM12 promotes the lung squamous cell carcinoma progression through mediating alternative splicing of ARRB1.Communications biology · 2025Article
- Cellular dsRNA interactome captured by K1 antibody reveals the regulatory map of exogenous RNA sensing.Communications biology · 2025Article
- Article
- Role of EPAC1 in chronic pain.Biochemistry and biophysics reports · 2024Review
- Suboptimal Mitochondrial Activity Facilitates Nuclear Heat Shock Responses for Proteostasis and Genome Stability.Molecules and cells · 2023Article
- Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation.Nature reviews. Drug discovery · 2023Review
- Endo-Lysosomal Two-Pore Channels and Their Protein Partners.Handbook of experimental pharmacology · 2023Review
- Unraveling the impact of disrupted nucleocytoplasmic transport systems inFrontiers in cellular neuroscience · 2023Review
- Physical Activity Rewires the Human Brain against Neurodegeneration.International journal of molecular sciences · 2022Article
- LSM12 facilitates the progression of colorectal cancer by activating the WNT/CTNNB1 signaling pathway.Oncology research · 2022Article
- ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD.Nucleic acids research · 2021Article
- Nuclear lamina invaginations are not a pathological feature of C9orf72 ALS/FTD.Acta neuropathologica communications · 2021Article
- Functional characterization of LSM12 as a driver in uveal melanoma oncogenesis.Advances in ophthalmology practice and researchArticle
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such as C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we identify a neuroprotective pathway of like-Sm protein 12 (LSM12) and exchange protein directly activated by cyclic AMP 1 (EPAC1) that sustains the nucleocytoplasmic RAN gradient and thereby suppresses NCT dysfunction by the C9ORF72-derived poly(glycine-arginine) protein. LSM12 depletion in human neuroblastoma cells aggravated poly(GR)-induced impairment of NCT and nuclear integrity while promoting the nuclear accumulation of poly(GR) granules. In fact, LSM12 posttranscriptionally up-regulated EPAC1 expression, whereas EPAC1 overexpression rescued the RAN gradient and NCT defects in LSM12-deleted cells. C9-ALS patient-derived neurons differentiated from induced pluripotent stem cells (C9-ALS iPSNs) displayed low expression of LSM12 and EPAC1. Lentiviral overexpression of LSM12 or EPAC1 indeed restored the RAN gradient, mitigated the pathogenic mislocalization of TDP-43, and suppressed caspase-3 activation for apoptosis in C9-ALS iPSNs. EPAC1 depletion biochemically dissociated RAN-importin β1 from the cytoplasmic nuclear pore complex, thereby dissipating the nucleocytoplasmic RAN gradient essential for NCT. These findings define the LSM12-EPAC1 pathway as an important suppressor of the NCT-related pathologies in C9-ALS/FTD.
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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 Socratic graph.