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Sulforaphane improves mitochondrial metabolism in fibroblasts from patients with fragile X-associated tremor and ataxia syndrome.

ABSTRACT: CGG expansions between 55 and 200 in the 5'-untranslated region of the fragile-X mental retardation gene (FMR1) increase the risk of developing the late-onset debilitating neuromuscular disease Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). While the science behind this mutation, as a paradigm for RNA-mediated nucleotide triplet repeat expansion diseases, has progressed rapidly, no treatment has proven effective at delaying the onset or decreasing morbidity, especially at later stages of the disease. Here, we demonstrated the beneficial effect of the phytochemical sulforaphane (SFN), exerted through NRF2-dependent and independent manner, on pathways relevant to brain function, bioenergetics, unfolded protein response, proteosome, antioxidant defenses, and iron metabolism in fibroblasts from FXTAS-affected subjects at all disease stages. This study paves the way for future clinical studies with SFN in the treatment of FXTAS, substantiated by the established use of this agent in clinical trials of diseases with NRF2 dysregulation and in which age is the leading risk factor.

SUBMITTER: Napoli E

PROVIDER: S-EPMC8475276 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

| S-EPMC4011071 | biostudies-literature

Women with Fragile X-associated Tremor/Ataxia Syndrome.

Project description:BackgroundFragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder linked to the FMR1 premutation.ObjectivesFXTAS in women is far less common than in men, and this study represents the largest sample reported to date.MethodsA total of 53 female premutation carriers with FXTAS (meanage, 66.83 years; FXTAS stages 2-5) and 55 age-matched and demographic background-matched control participants (meanage, 61.94 years) underwent a comprehensive molecular, physiological, neuropsychological, and psychiatric assessment.ResultsThe large sample of female premutation carriers showed a wide range of variability of clinical signs and symptom progression. The imaging results showed a middle cerebellar peduncles sign in only 6 patients; another symptom included high-signal intensity in the splenium of the corpus callosum, and diffuse cerebral deep white matter changes (e.g., in the pons) are more common. The rate of psychiatric disorders, especially depression, is higher than in the general population. There is a clear impairment in executive functioning and fine motor skills in connection with a higher FXTAS stage.ConclusionsThe manifestation of FXTAS symptoms in female carriers can be diverse with a milder phenotype and a lower penetrance than those observed in male premutation carriers. The middle cerebellar peduncles sign is present in only a small percentage of the sample, and we propose that the imaging criteria for FXTAS in women need to be expanded.

| S-EPMC7604678 | biostudies-literature

Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor/Ataxia Syndrome: a Pilot Study.

Project description:Currently, there is no effective treatment for the fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. In this pilot study, we evaluated whether allopregnanolone, a natural neurosteroid that exerts beneficial effects in neurodegenerative diseases, nervous system injury, and peripheral neuropathies, could improve lymphocytic bioenergetics and plasma pharmacometabolomics in six males with FXTAS (68?±?3 years old; FMR1 CGG repeats 94?±?4; FXTAS stages ranging from 3 to 5) enrolled in a 12-week open-label intervention study conducted at the University of California Davis from December 2015 through July 2016. Plasma pharmacometabolomics and lymphocytic mitochondria function were assessed at baseline (on the day of the first infusion) and at follow-up (within 48 h from the last infusion). In parallel, quantitative measurements of tremor and ataxia and neuropsychological evaluations of mental state, executive function, learning, memory, and psychological symptoms were assessed at the same time points. Allopregnanolone treatment impacted significantly GABA metabolism, oxidative stress, and some of the mitochondria-related outcomes. Notably, the magnitude of the individual metabolic response, as well as the correlation with some of the behavioral tests, was overwhelmingly carrier-specific. Based on this pilot study, allopregnanolone treatment has the potential for improving cognitive and GABA metabolism in FXTAS aligned with the concept of precision medicine.

| S-EPMC6401336 | biostudies-literature

Tremor-Predominant Fragile X-Associated Tremor/Ataxia Syndrome in a Female.

Project description: Not available

| S-EPMC6353491 | biostudies-literature

Molecular pathogenesis of fragile X-associated tremor/ataxia syndrome.

Project description:Fragile X-associated tremor/ataxia syndrome is a late adult onset neurodegenerative disorder that affects individuals who carry a premutation CGG repeat expansion (55-200 CGG repeats) in the 5' untranslated portion of the fragile X mental retardation 1 (FMR1) gene. Affected individuals display cognitive decline, progressive intention tremor, gait ataxia, neuropathy, psychiatric symptoms, and parkinsonism; the severity of both clinical and neuropathological phenotypes is positively correlated with the extent of the CGG expansion. Overexpression of the expanded CGG repeat messenger RNA results in a direct gain-of-function cellular toxicity that is believed to form the pathogenic basis for fragile X-associated tremor/ataxia syndrome. This mechanism is entirely different from the mechanism giving rise to fragile X syndrome, which is due to transcriptional silencing and consequent loss of FMR1 protein. Much of the research in the field has focused on understanding the link between the pathogenic FMR1 messenger RNA and the potential proteins that interact with it.

| S-EPMC2787679 | biostudies-literature

Cerebral Microbleeds in Fragile X-Associated Tremor/Ataxia Syndrome.

Project description:BackgroundFragile X-associated tremor/ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological features of neurodegeneration in fragile X-associated tremor/ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin-positive intranuclear inclusions, white matter disease, iron accumulation, and a proinflammatory state.ObjectiveThe objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X-associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X-associated tremor/ataxia syndrome.MethodsWe collected cerebral and cerebellar tissue from 15 fragile X-associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid β protein immunostaining. We quantified the number of cerebral microbleeds, amount of iron, presence of amyloid β within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis.ResultsWe found intranuclear inclusions in the endothelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X-associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capillaries that contain amyloid β in the cerebral cortex and the rate of disease progression.ConclusionWe propose microangiopathy as a pathologic feature of fragile X-associated tremor/ataxia syndrome. © 2021 International Parkinson and Movement Disorder Society.

| S-EPMC10929604 | biostudies-literature

Fragile X-associated Tremor/Ataxia Syndrome in an Adolescent Female.

Project description: Not available

| S-EPMC6353322 | biostudies-literature

Can a Neurosteroid Ameliorate Fragile X-Associated Tremor/Ataxia Syndrome?

Project description: Not available

| S-EPMC5722773 | biostudies-literature

Tremorography in fragile X-associated tremor/ataxia syndrome, Parkinson's disease and essential tremor.

Project description:BackgroundFragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease affecting carriers of a 55-200 CGG repeat in the fragile X mental retardation 1 gene, may receive an initial diagnosis of Parkinson's disease (PD) or essential tremor (ET) due to overlapping motor symptoms. Therefore, tremor and bradykinesia were compared in these disorders using quantitative tremorography.MethodsThe inertial sensor based Kinesia ™ system was used to quantify upper extremity tremor and bradykinesia in participants with FXTAS (n = 25), PD (n = 23), ET (n = 18) and controls (n = 20) and regression analysis was performed to determine whether tremorography measures distinguished between the groups. The FXTAS Rating scale (FXTAS-RS) was administered to determine whether sub-score items on the clinician rated scale correlated with tremorography variables.ResultsFXTAS participants had reduced finger tap speed compared to those with ET, and ET had increased kinetic tremor compared to PD. Higher kinetic tremor distinguished FXTAS from PD (p = .02), and lower finger tap speed distinguished FXTAS from ET (p = .004). FXTAS-RS tremor and bradykinesia items correlated with tremorography measures (p = .005 to <0.0001).ConclusionsThis is the first quantitative study to compare tremor and bradykinesia in FXTAS, PD and ET. Kinetic tremor and bradykinesia measures using a quantitative inertial sensor system distinguished FXTAS from PD and ET, respectively. Such technologies may be useful for detecting precise tremor and bradykinesia abnormalities and distinguishing the tremor and bradykinesia profiles in each of these disorders.

| S-EPMC8298795 | biostudies-literature

Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome.

Project description:Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects individuals who are carriers of small CGG premutation expansions in the fragile X mental retardation 1 (FMR1) gene. Mitochondrial dysfunction was observed as an incipient pathological process occurring in individuals who do not display overt features of FXTAS (1). Fibroblasts from premutation carriers had lower oxidative phosphorylation capacity (35% of controls) and Complex IV activity (45%), and higher precursor-to-mature ratios (P:M) of nDNA-encoded mitochondrial proteins (3.1-fold). However, fibroblasts from carriers with FXTAS symptoms presented higher FMR1 mRNA expression (3-fold) and lower Complex V (38%) and aconitase activities (43%). Higher P:M of ATPase ?-subunit (ATPB) and frataxin were also observed in cortex from patients that died with FXTAS symptoms. Biochemical findings observed in FXTAS cells (lower mature frataxin, lower Complex IV and aconitase activities) along with common phenotypic traits shared by Friedreich's ataxia and FXTAS carriers (e.g. gait ataxia, loss of coordination) are consistent with a defective iron homeostasis in both diseases. Higher P:M, and lower ZnT6 and mature frataxin protein expression suggested defective zinc and iron metabolism arising from altered ZnT protein expression, which in turn impairs the activity of mitochondrial Zn-dependent proteases, critical for the import and processing of cytosolic precursors, such as frataxin. In support of this hypothesis, Zn-treated fibroblasts showed a significant recovery of ATPB P:M, ATPase activity and doubling time, whereas Zn and desferrioxamine extended these recoveries and rescued Complex IV activity.

| S-EPMC3131047 | biostudies-literature

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