scholarly journals Near-cognate initiation generates FMRpolyG from CGG repeats in Fragile X associated Tremor Ataxia Syndrome

2020 ◽  
Author(s):  
Yuan Zhang ◽  
M. Rebecca Glineburg ◽  
Venkatesha Basrur ◽  
Kevin Conlon ◽  
Deborah A. Hall ◽  
...  
Keyword(s):  
Fragile X ◽  
Model Systems ◽  
Initiation Factor ◽  
Amino Terminal ◽  
Human Samples ◽  
Cgg Repeats ◽  
Cellular Environment ◽  
Ataxia Syndrome ◽  
Signature Peptides ◽  
Ran Translation

AbstractRepeat associated non-AUG (RAN) translation of FMR1 5’ UTR CGG repeats produces toxic homo-polymeric proteins that accumulate within ubiquitinated inclusions in Fragile X-associated tremor/ataxia syndrome (FXTAS) patient brains and model systems. The most abundant RAN product, FMRpolyG, initiates predominantly at an ACG codon located just 5’ to the repeat. Methods to accurately measure FMRpolyG in FXTAS patients are lacking. Here we used data dependent acquisition (DDA) and parallel reaction monitoring (PRM) mass spectrometry coupled with stable isotope labeled standard peptides (SIS) to identify potential signature FMRpolyG fragments in patient cells and tissues. Following immunoprecipitation (IP) enrichment, we detected FMRpolyG signature peptides by PRM in transfected cells, FXTAS human samples and patient derived stem cells, but not in controls. Surprisingly, we identified two amino-terminal peptides: one beginning with methionine (Ac-MEAPLPGGVR) initiating at an ACG, and a second beginning with threonine (Ac-TEAPLPGGVR), initiating at a GUG. Abundance of the threonine peptide was enhanced relative to the methionine peptide upon activation of the integrated stress response. In addition, loss of the eIF2 alternative factor, eIF2A, or enhanced expression of initiation factor eIF1, preferentially suppressed GUG initiated FMRpolyG synthesis. These data demonstrate that FMRpolyG is quantifiable in human samples and that RAN translation on FMR1 initiates at specific near cognate codons dependent on available initiation factors and cellular environment.

scholarly journals RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome

2015 ◽  
Vol 24 (15) ◽  
pp. 4317-4326 ◽  
Author(s):  
Seok Yoon Oh ◽  
Fang He ◽  
Amy Krans ◽  
Michelle Frazer ◽  
J. Paul Taylor ◽  
...  
Keyword(s):  
Fragile X ◽  
Ubiquitin Proteasome System ◽  
Cgg Repeats ◽  
Ubiquitin Proteasome ◽  
Ataxia Syndrome ◽  
Ran Translation

scholarly journals Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

2021 ◽  
Vol 22 (16) ◽  
pp. 8368
Author(s):  
Luis M. Valor ◽  
Jorge C. Morales ◽  
Irati Hervás-Corpión ◽  
Rosario Marín
Keyword(s):  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Fragile X ◽  
Endocrine System ◽  
Molecular Pathogenesis ◽  
Adult Women ◽  
Adult Men ◽  
Cgg Repeats ◽  
Reproductive Impairment ◽  
Ataxia Syndrome

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

scholarly journals CGG repeats in RNA modulate expression of TDP-43 in mouse and fly models of fragile X tremor ataxia syndrome

2014 ◽  
Vol 23 (22) ◽  
pp. 5906-5915 ◽  
Author(s):  
Jocelyn N. Galloway ◽  
Chad Shaw ◽  
Peng Yu ◽  
Deena Parghi ◽  
Mickael Poidevin ◽  
...  
Keyword(s):  
Fragile X ◽  
Cgg Repeats ◽  
Ataxia Syndrome

scholarly journals Delineating the Relationships Between Motor, Cognitive-Executive and Psychiatric Symptoms in Female FMR1 Premutation Carriers

2021 ◽  
Vol 12 ◽  
Author(s):  
Darren R. Hocking ◽  
Danuta Z. Loesch ◽  
Paige Stimpson ◽  
Flora Tassone ◽  
Anna Atkinson ◽  
...  
Keyword(s):  
Executive Functioning ◽  
Response Inhibition ◽  
Rating Scales ◽  
Psychiatric Symptoms ◽  
Fragile X ◽  
Fmr1 Premutation ◽  
Symptom Dimensions ◽  
Cgg Repeats ◽  
Cerebellar Peduncles ◽  
Ataxia Syndrome

Introduction: Premutation expansions (55–200 CGG repeats) of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome are associated with a range of clinical features. Apart from the most severe - Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) - where the most typical white matter changes affect cerebellar peduncles, more subtle changes may include impairment of executive functioning, affective disorders and/or subtle motor changes. Here we aimed to examine whether performance in selected components of executive functioning is associated with subclinical psychiatric symptoms in non-FXTAS, adult females carrying the FMR1 premutation.Methods and Sample: A total of 47 female premutation carriers (sub-symptomatic for FXTAS) of wide age range (26–77 years; M = 50.3; SD = 10.9) were assessed using standard neuropsychological tests, three motor rating scales and self-reported measures of psychiatric symptoms using the Symptom Checklist-90-Revised (SCL-90-R).Results: After adjusting for age and educational level where appropriate, both non-verbal reasoning and response inhibition as assessed on the Stroop task (i.e., the ability to resolve cognitive interference) were associated with a range of primary psychiatric symptom dimensions, and response inhibition uniquely predicted some primary symptoms and global psychiatric features. Importantly, lower scores (worse performance) in response inhibition were also strongly correlated with higher (worse) scores on standard motor rating scales for tremor-ataxia and for parkinsonism.Conclusion: These results provide evidence for the importance of response inhibition in the manifestation of psychiatric symptoms and subtle tremor-ataxia motor features, suggestive of the presence of early cerebellar changes in female premutation carriers.

scholarly journals Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

Neuron ◽  
2017 ◽  
Vol 93 (2) ◽  
pp. 331-347 ◽  
Author(s):  
Chantal Sellier ◽  
Ronald A.M. Buijsen ◽  
Fang He ◽  
Sam Natla ◽  
Laura Jung ◽  
...  
Keyword(s):  
Fragile X ◽  
Cgg Repeats ◽  
Ataxia Syndrome

scholarly journals Early Onset of Fragile X Associated Tremor and Ataxia Syndrome: A Case Report from Iran

2021 ◽  
Vol 7 (3) ◽  
pp. 180-183
Author(s):  
Shahin Koohmanaee ◽  
◽  
Fatemeh Kharaee ◽  
Reza Bayat ◽  
Maryam Shahrokhi ◽  
...  
Keyword(s):  
Early Onset ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Case Presentation ◽  
Old Adults ◽  
Cgg Repeats ◽  
Clinical Presentations ◽  
Ataxia Syndrome ◽  
Magnetic Resonance Imaging Mri ◽  
First Time

Background: Different alleles of Fragile X Mental Retardation1 (FMR1) gene with separate molecular etiologies cause Fragile X Syndrome (FXS) and Fragile X-associated Tremor and Ataxia Syndrome (FXTAS). Premutation alleles with 55 to 200 repeats in the FMR1 gene lead to FXTAS. It is carried by 1 in 209 women and 1 in 430 men. FXTAS commonly appears in 50- to 70-year-old adults. Case Presentation: An 11 months old boy was referred to the hospital due to clinical presentations of productive cough seizure, mental disability, and ataxia. Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), hematology, biochemistry, hormone, and genetic tests were done. Triplet repeat PCR (TP PCR) showed 99 CGG repeats as permutation alleles. Conclusion: In this study, the authors reported the early onset of FXTAS in an 11 months old boy for the first time.

Mechanistic Convergence Across Initiation Sites for RAN Translation in Fragile X Associated Tremor Ataxia Syndrome

2021 ◽  
Author(s):  
Yuan Zhang ◽  
M. Rebecca Glineburg ◽  
Venkatesha Basrur ◽  
Kevin P. Conlon ◽  
Shannon E. Wright ◽  
...  
Keyword(s):  
Fragile X ◽  
Ataxia Syndrome ◽  
Ran Translation

scholarly journals Fragile X-associated tremor ataxia syndrome with co-occurrent progressive supranuclear palsy-like neuropathology

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Amanda N. Sacino ◽  
Stefan Prokop ◽  
Meggen A. Walsh ◽  
Jennifer Adamson ◽  
S. H. Subramony ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Patient Management ◽  
Fragile X ◽  
Brain Regions ◽  
Nuclear Inclusions ◽  
Common Phenomenon ◽  
Pathological Changes ◽  
Tau Pathology ◽  
Ataxia Syndrome ◽  
Ran Translation

Abstract Co-occurrence of multiple neuropathologic changes is a common phenomenon, most prominently seen in Alzheimer’s disease (AD) and Parkinson’s disease (PD), complicating clinical diagnosis and patient management. Reports of co-occurring pathological processes are emerging in the group of genetically defined repeat-associated non-AUG (RAN)-translation related diseases. Here we report a case of Fragile X-associated tremor-ataxia syndrome (FXTAS) with widespread and abundant nuclear inclusions of the RAN-translation related FMRpolyG-peptide. In addition, we describe prominent neuronal and glial tau pathology representing changes seen in progressive supranuclear palsy (PSP). The highest abundance of the respective pathological changes was seen in distinct brain regions indicating an incidental, rather than causal correlation.

scholarly journals CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome

2021 ◽  
Vol 7 (3) ◽  
pp. eabd9440
Author(s):  
Sefan Asamitsu ◽  
Yasushi Yabuki ◽  
Susumu Ikenoshita ◽  
Kosuke Kawakubo ◽  
Moe Kawasaki ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Aminolevulinic Acid ◽  
Fragile X ◽  
Protoporphyrin Ix ◽  
Neuronal Dysfunction ◽  
Cgg Repeat ◽  
Repeat Expansions ◽  
Ataxia Syndrome ◽  
And Behavior ◽  
Ran Translation

Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in FMR1, which elicit repeat-associated non-AUG (RAN) translation and produce the toxic protein FMRpolyG. We show that FMRpolyG interacts with pathogenic CGG repeat-derived RNA G-quadruplexes (CGG-G4RNA), propagates cell to cell, and induces neuronal dysfunction. The FMRpolyG polyglycine domain has a prion-like property, preferentially binding to CGG-G4RNA. Treatment with 5-aminolevulinic acid, which is metabolized to protoporphyrin IX, inhibited RAN translation of FMRpolyG and CGG-G4RNA–induced FMRpolyG aggregation, ameliorating aberrant synaptic plasticity and behavior in FXTAS model mice. Thus, we present a novel therapeutic strategy to target G4RNA prionoids.

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