ArticleActa neuropathologica communications2019
Neuropathology of RAN translation proteins in fragile X-associated tremor/ataxia syndrome.
Article in Acta neuropathologica communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 59 citations in OpenAlex.
- Relationships between Mitochondrial Function, AMPK, and TORC1 Signaling in Lymphoblasts with Premutation Alleles of the FMR1 Gene.International journal of molecular sciences · 2021Trial
- The role of FMR1 mRNA structure on the efficiency of non-canonical translation of toxic polyglycine protein.Nucleic acids research · 2026Article
- Translation of expanded CGG repeats in LRP12 associated oculopharyngodistal myopathy.Acta neuropathologica communications · 2026Article
- Article
- Integrative transcriptome-wide association analyses reveal PRKCG-linked GABAergic dysfunction in Fragile X-associated tremor/ataxia syndrome.Nature communications · 2026Article
- IGF2BPs directly regulate the noncanonical translation of toxic proteins from mutant FMR1 mRNA containing expanded CGG repeats.Nature communications · 2025Article
- Recent progress in oculopharyngodistal myopathy research from clinical and genetic viewpoints.Journal of neuromuscular diseases · 2025Review
- Advances on the Mechanisms and Therapeutic Strategies in Non-coding CGG Repeat Expansion Diseases.Molecular neurobiology · 2024Review
- AAGGG repeat expansions triggerScience advances · 2024Article
- A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.Nature genetics · 2024Article
- Case Series: Vestibular Migraines in Fragile X Premutation Carriers.Journal of clinical medicine · 2024Article
- Review
- Abnormal phase separation of biomacromolecules in human diseases.Acta biochimica et biophysica Sinica · 2023Review
- Native functions of short tandem repeats.eLife · 2023Article
- Between Order and Chaos: Understanding the Mechanism and Pathology of RAN Translation.Biological & pharmaceutical bulletin · 2023Review
- Expression of expanded GGC repeats withinScience advances · 2022Article
- Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain-of-function toxicity mechanism contributing to the pathogenesis of fragile X-associated premature ovarian insufficiency.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- CGG repeats trigger translational frameshifts that generate aggregation-prone chimeric proteins.Nucleic acids research · 2022Article
- Mechanistic convergence across initiation sites for RAN translation in fragile X associated tremor ataxia syndrome.Human molecular genetics · 2022Article
- Clinical and mechanism advances of neuronal intranuclear inclusion disease.Frontiers in aging neuroscience · 2022Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
CGG repeat expansions in FMR1 cause the neurodegenerative disorder Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Ubiquitinated neuronal intranuclear inclusions (NIIs) are the neuropathological hallmark of FXTAS. Both sense strand derived CGG repeats and antisense strand derived CCG repeats support non-AUG initiated (RAN) translation of homopolymeric proteins in potentially 6 different reading frames. However, the relative abundance of these proteins in FXTAS brains and their co-localization with each other and NIIs is lacking. Here we describe rater-blinded assessment of immunohistochemical and immunofluorescence staining with newly generated antibodies to different CGG RAN translation products in FXTAS and control brains as well as co-staining with ubiquitin, p62/SQSTM1, and ubiquilin 2. We find that both FMRpolyG and a second CGG repeat derived RAN translation product, FMRpolyA, accumulate in aggregates in FXTAS brains. FMRpolyG is a near-obligate component of both ubiquitin-positive and p62-positive NIIs in FXTAS, with occurrence of aggregates in 20% of all hippocampal neurons and > 90% of all inclusions. A subset of these inclusions also stain positive for the ALS/FTD associated protein ubiquilin 2. Ubiquitinated inclusions and FMRpolyG+ aggregates are rarer in cortex and cerebellum. Intriguingly, FMRpolyG staining is also visible in control neuronal nuclei. In contrast to FMRpolyG, staining for FMRpolyA and CCG antisense derived RAN translation products were less abundant and less frequent components of ubiquitinated inclusions. In conclusion, RAN translated FMRpolyG is a common component of ubiquitin and p62 positive inclusions in FXTAS patient brains.
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