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

Napoli, Eleonora; Flores, Amanda; Mansuri, Yasmeen; Hagerman, Randi J.; Giulivi, Cecilia R

doi:10.1016/j.nbd.2021.105427

Cited by 14 publications

(17 citation statements)

References 156 publications

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“…At the mechanistic level, our findings of mitochondrial dysfunction in the premutation may be explained by recent reports on fragile X syndrome's models (contrary to the premutation, there is no detectable FMR1 gene or FMRP protein expression in males and reduced FMRP expression in females), in which FMRP was found to regulate mitochondrial mRNA expression and energy homeostasis (murine model), and energy metabolism and mitochondrial function (Drosophila model) [79,80]. A recent study by our team provides further support for proteotoxicity and altered unfolded protein response at the core of the bioenergetic deficits in FXTAS [18,22,81,82], as sulforaphane-mediated normalization of these processes recovered mitochondrial function [82].…”

Section: Discussionmentioning

confidence: 69%

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

Wang

Napoli

Kim

et al. 2021

IJMS

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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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Section: Discussionmentioning

confidence: 69%

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

Wang

Napoli

Kim

et al. 2021

IJMS

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“…However, more comprehensive long-term studies are needed, as many of the controlled trials are of low quality with industry funding. Sulforaphane is another dietary supplement with antioxidant/anti-inflammatory properties that was found to improve markers of oxidative stress and mitochondrial function in fibroblasts from FXTAS patients ( 87 ), but has not been studied for pain symptoms in FXTAS.…”

Section: Discussionmentioning

confidence: 99%

Increased Pain Symptomatology Among Females vs. Males With Fragile X-Associated Tremor/Ataxia Syndrome

et al. 2022

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Individuals with the fragile X premutation report symptoms of chronic pain from multiple systems, have increased incidence of comorbid conditions where pain is a prominent feature, and pathophysiology that supports disrupted pain regulation, inflammation, and energy imbalance. Less is known about how pain manifests for the subpopulation of carriers that develop the motor and cognitive changes of fragile X-associated tremor and ataxia syndrome (FXTAS), and how pain may differ between men and women. We gathered data collected from 104 males and females with FXTAS related to chronic pain, comorbid conditions related to pain, and medications used for pain control to further explore the types of pain experienced and to better characterize how individuals with the fragile X premutation experience pain sensation across genders. We found that women experience significantly more pain symptoms than men, particularly allodynia (20 vs. 2.0%, p = 0.008), peripheral neuropathy pain (43.9 vs. 25.4%, p = 0.0488), migraine (43.9 vs. 14.5%, p = 0.0008), fibromyalgia (26.8 vs. 0%, p = 0.0071) and back pain (48.5 vs. 23.4%, p = 0.008). We found onset of peripheral neuropathy predicts the onset of ataxia (β = 0.63 ± 0.25, p = 0.019) and tremor (β = 0.56 ± 0.17, p = 0.004) across gender. Women also report significantly more anxiety (82.9 vs. 39.7%, p < 0.001), which has implications for ideal pain treatment. These pain symptoms need to be recognized in the medical history and treated appropriately, with consideration for overlapping comorbidities.

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“…Furthermore, considering the critical role mitochondria play in neurotransmitter metabolism 28 , 29 , 38 , it is not surprising that mitochondrial deficits likely compound the proteo- and RNA-triggered toxicities in CNS, contributing to FXTAS morbidity progression. This is well exemplified by our study of sulforaphane-treated fibroblasts from carriers at late stages whose bioenergetics were recovered by controlling their unfolded protein response and antioxidant capacities 39 . Although in vitro overexpression of the repeat-associated non-AUG (RAN)-mediated FMRpolyG product resulted in mitochondrial dysfunction 40 , no significant FMRpolyG levels in biospecimens from carriers have been found 41 , 42 even with evident mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 77%

Artificial neural network applied to fragile X-associated tremor/ataxia syndrome stage diagnosis based on peripheral mitochondrial bioenergetics and brain imaging outcomes

Giulivi

Wang

Hagerman

2022

Sci Rep

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No proven prognosis is available for the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Artificial neural network analyses (ANN) were used to predict FXTAS progression using data from 127 adults (noncarriers and FMR1 premutation carriers with and without FXTAS) with five outcomes from brain MRI imaging and 22 peripheral bioenergetic outcomes from two cell types. Diagnosis accuracy by ANN predictions ranged from 41.7 to 86.3% (depending on the algorithm used), and those misclassified usually presented a higher FXTAS stage. ANN prediction of FXTAS stages was based on a combination of two imaging findings (white matter hyperintensity and whole-brain volumes adjusted for intracranial volume) and four bioenergetic outcomes. Those at Stage 3 vs. 0–2 showed lower mitochondrial mass, higher oxidative stress, and an altered electron transfer consistent with mitochondrial unfolded protein response activation. Those at Stages 4–5 vs. 3 had higher oxidative stress and glycerol-3-phosphate-linked ATP production, suggesting that targeting mGPDH activity may prevent a worse prognosis. This was confirmed by the bioenergetic improvement of inhibiting mGPDH with metformin in affected fibroblasts. ANN supports the prospect of an unbiased molecular definition in diagnosing FXTAS stages while identifying potential targets for personalized medicine.

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

Cited by 14 publications

References 156 publications

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

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

Increased Pain Symptomatology Among Females vs. Males With Fragile X-Associated Tremor/Ataxia Syndrome

Artificial neural network applied to fragile X-associated tremor/ataxia syndrome stage diagnosis based on peripheral mitochondrial bioenergetics and brain imaging outcomes

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