CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome

Todd, Peter K.; Oh, Seok Yoon; Krans, Amy; He, Fei; Sellier, Chantal; Frazer, Michelle; Renoux, Abigail J.; Chen, Kai-chun; Scaglione, K. Matthew; Basrur, Venkatesha; Elenitoba‐Johnson, Kojo S.J.; Vonsattel, Jean Paul; Louis, Elan D.; Sutton, Michael A.; Taylor, J. Paul; Mills, Ryan E.; Charlet‐Berguerand, Nicolas; Paulson, Henry L.

doi:10.1016/j.neuron.2013.07.008

Cited by 42 publications

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“…79 In the current instance, Todd et al 78 have provided ample evidence that RAN translation of the FMR1 mRNA generates a poly-glycine peptide that is toxic to cells and is detectable in both the intranuclear inclusions of FXTAS and in the inclusions of the Dutch premutation CGG-repeat mouse model (see Refs 19 and 78 ). However, the role of the poly-glycine peptides in FXTAS remains an open question, given that a highly related mouse model, termed the "NIH" model, 78, 80 displays significant neurodegeneration but apparently does not produce the poly-glycine peptide because of a stop codon just downstream of the initiating codon for the that peptide. 78 These seemingly paradoxical observations may indicate that the nuclear inclusions are themselves a consequence of RAN translation, but that the FXTAS-associated neurodegeneration is due to other mechanisms-this is an important area for further study.…”

Section: Repeat-associated Non-aug (Ran) Translationmentioning

confidence: 95%

Section: Repeat-associated Non-aug (Ran) Translationmentioning

confidence: 99%

“…1); 78 RAN translation has been well described in other trinucleotide-repeat disorders. 79 In the current instance, Todd et al 78 have provided ample evidence that RAN translation of the FMR1 mRNA generates a poly-glycine peptide that is toxic to cells and is detectable in both the intranuclear inclusions of FXTAS and in the inclusions of the Dutch premutation CGG-repeat mouse model (see Refs 19 and 78 ). However, the role of the poly-glycine peptides in FXTAS remains an open question, given that a highly related mouse model, termed the "NIH" model, 78, 80 displays significant neurodegeneration but apparently does not produce the poly-glycine peptide because of a stop codon just downstream of the initiating codon for the that peptide.…”

Section: Repeat-associated Non-aug (Ran) Translationmentioning

confidence: 99%

“…However, the role of the poly-glycine peptides in FXTAS remains an open question, given that a highly related mouse model, termed the "NIH" model, 78, 80 displays significant neurodegeneration but apparently does not produce the poly-glycine peptide because of a stop codon just downstream of the initiating codon for the that peptide. 78 These seemingly paradoxical observations may indicate that the nuclear inclusions are themselves a consequence of RAN translation, but that the FXTAS-associated neurodegeneration is due to other mechanisms-this is an important area for further study.…”

Section: Repeat-associated Non-aug (Ran) Translationmentioning

confidence: 99%

See 3 more Smart Citations

Fragile X-associated tremor/ataxia syndrome

Leehey

Hagerman

2012

Handbook of Clinical Neurology

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Section: Repeat-associated Non-aug (Ran) Translationmentioning

confidence: 95%

Section: Repeat-associated Non-aug (Ran) Translationmentioning

confidence: 99%

Section: Repeat-associated Non-aug (Ran) Translationmentioning

confidence: 99%

Section: Repeat-associated Non-aug (Ran) Translationmentioning

confidence: 99%

See 2 more Smart Citations

Fragile X-associated tremor/ataxia syndrome

Leehey

Hagerman

2012

Handbook of Clinical Neurology

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“…1). The mechanism of RAN translation likely involves inefficient RNA splicing and stalling of the ribosome as it scans the hexanucleotide repeat, leading to inappropriate translation without a start codon [134,135]. The G 4 C 2 repeat is translated in all reading frames in both the sense and antisense strands, resulting in several different dipeptides that accumulate specifically within the cells of patients carrying pathogenic (>22) repeat lengths.…”

Section: Alternative Rna-based Mechanismsmentioning

confidence: 99%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

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The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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Neuropathology of FMR1‐premutation carriers presenting with dementia and neuropsychiatric symptoms

Dijkstra

Haify

Verwey

et al. 2020

Alzheimer's & Dementia

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Background CGG repeat expansions in the premutation range (55‐200) of the FMR1 gene can lead to Fragile‐X associated tremor/ataxia syndrome (FXTAS). Clinically, FXTAS is characterized by progressive tremor and ataxia, however psychiatric symptoms can also manifest as part of the syndrome, termed Fragile‐X associated neuropsychiatric disorders (FXAND) (1). Pathology of FXTAS/FXAND include ubiquitin‐positive intranuclear inclusions in both neurons and glia cells. Recently, FMRpolyG RAN‐translation product has been identified in the majority of the inclusions (2). Method Here, we describe two cases with predominantly FXAND symptoms with mild movement disturbances. One donor was diagnosed with vascular dementia and frontotemporal dementia during life carrying an 107 CGG repeat expansion in the FMR1 gene. Donor two, carrying an 77 repeat expansion, presented with dementia and behavior alterations, and suffered from several infarcts throughout the brain. Result Macroscopically, both donors showed no FXTAS‐characteristic white matter lesions on MRI, but vascular infarcts in cortical‐ and subcortical regions were identified. At microscopic level, vascular pathology was observed throughout the brain. A high number of p62‐positive intranuclear inclusions were observed predominantly in cortical regions in neuronal, glial, ependymal, choroid plexus and endothelial cells. The majority of these inclusions were positive for FMRpolyG as well. Dopaminergic neurons in the substantia nigra contained p62‐positive intranuclear inclusions, but were FMRpolyG negative. Conclusion We conclude that in these patients with FXAND, no characteristic MRI abnormalities are seen and that the inclusion pathology of FXAND also affects the vasculature of the brain. Inclusions were present in large numbers throughout the brain, and often positive for FMRpolyG. The described donors clinically resemble other types of dementia, and in absence of genetic testing or family history, FMRpolyG can be used post‐mortem to identify premutation carriersHagerman et al. Fragile X‐Associated Neuropsychiatric Disorders (FXAND) Front. Psychiatry. 2018. (2) Krans et al. Neuropathology of RAN translation proteins in fragile X‐associated tremor/ataxia syndrome Acta Neuropathol Commun. 2019.

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CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome

Cited by 42 publications

References 0 publications

Fragile X-associated tremor/ataxia syndrome

Fragile X-associated tremor/ataxia syndrome

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Neuropathology of FMR1‐premutation carriers presenting with dementia and neuropsychiatric symptoms

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