Altered Redox Mitochondrial Biology in the Neurodegenerative Disorder Fragile X-Tremor/Ataxia Syndrome: Use of Antioxidants in Precision Medicine

Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that manifests with intention tremor, progressive gait ataxia, and cognitive impairment. The disease is genetically characterized by a premutation of the <i>FMR1</i>gene on the X-chromosome manifesting with a CGG triplet expansion between 55 and 200. Given the phenotypical variety of this disease, diagnosis is frequently delayed. We present and discuss a male patient whose diagnosis of FXTAS was delayed due to his concomitant alcohol abuse.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22168368 ◽

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.

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Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.600840 ◽

2021 ◽

Vol 7 ◽

Author(s):

Katharine Nichole Holm ◽

Anthony W. Herren ◽

Sandra L. Taylor ◽

Jamie L. Randol ◽

Kyoungmi Kim ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Structural Integrity ◽

Rna Binding ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Protein Abundance ◽

Cgg Repeat ◽

Phosphoserine Aminotransferase ◽

Brain Volume Loss ◽

Ataxia Syndrome

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation CGG-repeat expansions (55–200 repeats) in the 5′ non-coding portion of the fragile X mental retardation 1 (FMR1) gene. Core features of FXTAS include progressive tremor/ataxia, cognitive decline, variable brain volume loss, and white matter disease. The principal histopathological feature of FXTAS is the presence of central nervous system (CNS) and non-CNS intranuclear inclusions.Objective: To further elucidate the molecular underpinnings of FXTAS through the proteomic characterization of human FXTAS cortexes.Results: Proteomic analysis of FXTAS brain cortical tissue (n = 8) identified minor differences in protein abundance compared to control brains (n = 6). Significant differences in FXTAS relative to control brain predominantly involved decreased abundance of proteins, with the greatest decreases observed for tenascin-C (TNC), cluster of differentiation 38 (CD38), and phosphoserine aminotransferase 1 (PSAT1); proteins typically increased in other neurodegenerative diseases. Proteins with the greatest increased abundance include potentially novel neurodegeneration-related proteins and small ubiquitin-like modifier 1/2 (SUMO1/2). The FMRpolyG peptide, proposed in models of FXTAS pathogenesis but only identified in trace amounts in the earlier study of FXTAS inclusions, was not identified in any of the FXTAS or control brains in the current study.Discussion: The observed proteomic shifts, while generally relatively modest, do show a bias toward decreased protein abundance with FXTAS. Such shifts in protein abundance also suggest altered RNA binding as well as loss of cell–cell adhesion/structural integrity. Unlike other neurodegenerative diseases, the proteome of end-stage FXTAS does not suggest a strong inflammation-mediated degenerative response.

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Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS

International Journal of Molecular Sciences ◽

10.3390/ijms22179171 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9171

Author(s):

Junyi Wang ◽

Eleonora Napoli ◽

Kyoungmi Kim ◽

Yingratana A. McLennan ◽

Randi J. Hagerman ◽

...

Keyword(s):

White Matter ◽

Brain Volume ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Mitochondrial Bioenergetics ◽

Mri Findings ◽

Mitochondrial Mass ◽

Atp Production ◽

Age Dependent ◽

Ataxia Syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5′UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH2-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH2-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings—and the lack of correlations with FXTAS diagnosis/stages—may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings.

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Genetic and Pathological Characteristic Patterns of a Family With Neuronal Intranuclear Inclusion Disease

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa142 ◽

2020 ◽

Vol 79 (12) ◽

pp. 1293-1302

Author(s):

Shugang Zhang ◽

Qixing Gong ◽

Di Wu ◽

Yun Tian ◽

Lu Shen ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Fragile X ◽

Cerebrovascular Diseases ◽

Pathological Examination ◽

Positive Staining ◽

Intranuclear Inclusion ◽

Cgg Repeats ◽

Genetic Features ◽

Neuronal Intranuclear Inclusion ◽

Ataxia Syndrome

Abstract Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder. This study aimed to investigate clinical, imaging, genetic, and dermatopathological characteristics of a family with adult-onset NIID. The proband was a 62-year-old woman with 3 brothers and 2 sisters. Of these, 4 had symptoms of paroxysmal visual field defect, extrapyramidal symptoms, dysautonomia, emotional changes, and cognitive dysfunction. Genetic examination revealed no abnormality related to cerebrovascular diseases. More than 200 CGG repeats of FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) whereas repeats of the proband were found 29 times, which excluded FXTAS. Quantitative reverse transcription polymerase chain reaction (PCR) and GC-rich-PCR identified an expanded GGC repeat (with ∼100 repeats) in the 5′ region of NOTCH2NLC in the patient and her 2 younger brothers. Pathological examination found eosinophilic intranuclear inclusions inside adipocytes, fibrocytes, and sweat gland cells. Immunohistochemistry and immunofluorescence staining revealed positive staining for ubiquitin and p62. The detailed pathological and genetic features of this NIID family provide a valuable contribution to the existing knowledge base of this rare disorder.

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Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Biochemical Journal ◽

10.1042/bj20091960 ◽

2010 ◽

Vol 429 (3) ◽

pp. 545-552 ◽

Cited By ~ 104

Author(s):

Catherine Ross-Inta ◽

Alicja Omanska-Klusek ◽

Sarah Wong ◽

Cedrick Barrow ◽

Dolores Garcia-Arocena ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Fragile X ◽

Mitochondrial Protein ◽

Additional Treatment ◽

Cgg Repeat ◽

Cgg Repeats ◽

Nitrative Stress ◽

Ataxia Syndrome

FXTAS (fragile X-associated tremor/ataxia syndrome) is a late-onset neurodegenerative disorder that affects individuals who are carriers of premutation expansions (55–200 CGG repeats) in the 5′ untranslated region of the FMR1 (fragile X mental retardation 1) gene. The role of MD (mitochondrial dysfunction) in FXTAS was evaluated in fibroblasts and brain samples from premutation carriers with and without FXTAS symptoms, with a range of CGG repeats. This study resulted in several important conclusions: (i) decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers; (ii) a lower expression of mitochondrial proteins preceded both in age and in CGG repeats the appearance of overt clinical involvement; (iii) the CGG repeat size required for altered mitochondrial protein expression was also smaller than that required to produce brain intranuclear inclusions from individuals with the premutation who died, suggesting that MD is an incipient pathological process occurring in individuals who do not display overt features of FXTAS; and (iv) on the basis of the CGG repeats, MD preceded the increase in oxidative/nitrative stress damage, indicating that the latter is a late event. MD in carriers of small CGG repeats, even when the allele size is not sufficient to produce FXTAS, may predispose them to other disorders (e.g. Parkinson's disease) that are likely to involve MD, and to environmental stressors, which may trigger the development of FXTAS symptoms. Detection of MD is of critical importance to the management of FXTAS, since it opens up additional treatment options for this disorder.

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Neuropathology of RAN translation proteins in Fragile X-associated Tremor/Ataxia Syndrome

10.1101/672444 ◽

2019 ◽

Cited By ~ 1

Author(s):

Amy Krans ◽

Geena Skariah ◽

Yuan Zhang ◽

Bryana Bayly ◽

Peter K. Todd

Keyword(s):

Hippocampal Neurons ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Antisense Strand ◽

Common Component ◽

Cgg Repeat ◽

Neuronal Nuclei ◽

Sense Strand ◽

Ataxia Syndrome ◽

Ran Translation

AbstractCGG 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 were infrequent components of FMRpolyG+ inclusions. In conclusion, RAN translated FMRpolyG is a common component of ubiquitin and p62 positive inclusions in FXTAS patient brains.

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Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

International Journal of Molecular Sciences ◽

10.3390/ijms21124391 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4391

Author(s):

Ana Maria Cabal-Herrera ◽

Nattaporn Tassanakijpanich ◽

Maria Jimena Salcedo-Arellano ◽

Randi J. Hagerman

Keyword(s):

Neurodegenerative Disorder ◽

Fragile X ◽

Cgg Repeats ◽

Mri Features ◽

Fmr1 Mrna ◽

Cerebellar Peduncles ◽

History Of ◽

Ataxia Syndrome ◽

Psychiatric Problems ◽

Female Carriers

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

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Neuropathology of RAN translation proteins in fragile X-associated tremor/ataxia syndrome

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0782-7 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Amy Krans ◽

Geena Skariah ◽

Yuan Zhang ◽

Bryana Bayly ◽

Peter K. Todd

Keyword(s):

Hippocampal Neurons ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Antisense Strand ◽

Common Component ◽

Cgg Repeat ◽

Neuronal Nuclei ◽

Sense Strand ◽

Ataxia Syndrome ◽

Ran Translation

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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Monoclonal Gammopathy of Undetermined Significance (MGUS) in a Man with Fragile X-associated Tremor/Ataxia Syndrome

Case Reports in Genetics ◽

10.1155/2011/143132 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5

Author(s):

Tanjung A. Sumekar ◽

Aneel A. Ashrani ◽

Tri I. Winarni ◽

Randi J. Hagerman

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Clinical Presentation ◽

Neurodegenerative Disorder ◽

Fragile X ◽

Laboratory Findings ◽

Ataxia Syndrome ◽

Undetermined Significance

We report the clinical presentation and laboratory findings of a 69-year-old man with fragile X-associated tremor ataxia syndrome (FXTAS), a progressive neurodegenerative disorder, who was noted to have monoclonal gammopathy of undetermined significance (MGUS), a plasma cell proliferative disorder and a precursor disease of multiple myeloma. Both MGUS and FXTAS are associated with microRNA (miRNA) dysregulation. We speculate that individuals with FXTAS may be predisposed to MGUS and further studies are warranted regarding this association.

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