ArticleActa neuropathologica2021
Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: implications for polyglycine diseases.
Article in Acta neuropathologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 2 of them syntheses that pooled it.
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Who cites it
45 citing papers in PubMed, 2 syntheses or guidelines pooled it, 67 citations in OpenAlex.
- Neuronal intranuclear inclusion disease with stroke-mimicking onset: a case report and systematic review.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Pooled it
- Advances of NOTCH2NLC Repeat Expansions and Associated Diseases: A Bibliometric and Meta-analysis.Molecular neurobiology · 2024Pooled it
- 5PSeq Explorer: interactive analysis of co-translational mRNA decay and ribosome dynamics.RNA biology · 2026Article
- Structural Polymorphism of polyG Inclusions Revealed by In Situ Cryo-Electron Tomography.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Expanded Polyglycine Protein Aggregates Alter the RNA Splicing Profile into a Premature State Partially via Sequestering SF3B4.Neuroscience bulletin · 2026Article
- A Second Pathogenic Protein, PolyGN2C-iso2, Reveals a Dual-Protein Pathology in Neuronal Intranuclear Inclusion Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Distinctive hydrocephalus-like phenotype in NOTCH2NLC-related neuronal intranuclear inclusion disease: clinicopathological features and therapeutic implications.Acta neuropathologica communications · 2026Article
- Subclinical peripheral nerve demyelination without overt symptoms in a family with neuronal intranuclear inclusion disease harboring biallelic repeat expansions.BMC neurology · 2026Article
- ASO therapy rescues NOTCH2NLC GGC repeat expansion-induced genomic damage, 3D chromatin structural abnormalities, and senescence.Nature communications · 2026Article
- The Hsp40 cochaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.The Journal of biological chemistry · 2026Article
- Translation of expanded CGG repeats in LRP12 associated oculopharyngodistal myopathy.Acta neuropathologica communications · 2026Article
- The Tale of the Guanosine Tract in Repeat Expansion Disorders.Molecular neurobiology · 2026Review
- GGC repeat expansions within new open reading frames are translated into toxic polyglycine proteins in oculopharyngodistal myopathy.Nature genetics · 2026Article
- PML targets and resolves structured protein inclusions to mitigate neurodegeneration.Nature cell biology · 2026Article
- Precise excision of expanded GGC repeats in NOTCH2NLC via CRISPR/Cas9 for treating neuronal intranuclear inclusion disease.Nature communications · 2026Article
- Evolutionary implications ofBrain communications · 2026Article
- Modeling neuronal intranuclear inclusion disease: A review of animal and human-derived cellular models and mechanistic insights.Zoological research · 2025Review
- Inflammation in Neuronal Intranuclear Inclusion Disease (NIID): mechanisms, biomarkers, and therapeutic implications.Journal of neuroinflammation · 2025Review
- HnRNP M expression rescues neurodegeneration in neuronal intranuclear inclusion disease mouse model by restoring dysregulated RNA splicing and transcription.Cell & bioscience · 2025Article
- Type B Fibers: A Novel Ultrastructural Biomarker for Cognitive Impairment in Neuronal Intranuclear Inclusion Disease.Brain sciences · 2025Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neuronal intranuclear inclusion disease (NIID) is neurodegenerative disease characterized by widespread inclusions. Despite the identification of GGC repeat expansion in 5'UTR of NOTCH2NLC gene in adult-onset NIIDs, its pathogenic mechanism remains unclear. Gain-of-function poly-amino-acid proteins generated by unconventional translation have been revealed in nucleotide repeat expansion disorders, inspiring us to explore the possibility of unconventional translation in NIID. Here we demonstrated that NOTCH2NLC 5'UTR triggers the translation of a polyglycine (polyG)-containing protein, N2NLCpolyG. N2NLCpolyG accumulates in p62-positive inclusions in cultured cells, mouse models, and NIID patient tissues with NOTCH2NLC GGC expansion. Translation of N2NLCpolyG is initiated by an upstream open reading frame (uORF) embedding the GGC repeats. N2NLCpolyG tends to aggregate with the increase of GGC repeat units, and displays phase separation properties. N2NLCpolyG aggregation impairs nuclear lamina and nucleocytoplasmic transport but does not necessarily cause acute death on neuronal cells. Our study suggests a similarity of pathogenic mechanisms between NIID and another GGC-repeat disease, fragile X-associated tremor ataxia syndrome. These findings expand our knowledge of protein gain-of-function in NIID, and further highlight evidence for a novel spectrum of diseases caused by aberrant polyG protein aggregation, namely the polyG diseases.
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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.