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Mol Med. 2016 Oct;22:548-559. doi: 10.2119/molmed.2016.00122. Epub 2016 Jun 30.

Altered redox mitochondrial biology in the neurodegenerative disorder fragile X-tremor/ataxia syndrome: use of antioxidants in precision medicine.

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Department of Molecular Biosciences, School of Veterinary Medicine, Davis, CA 95616.
Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, CA 95817.
Department of Pediatrics, University of California Davis Medical Center, Sacramento CA 95817.
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817.


A 55-200 expansion of the CGG nucleotide repeat in the 5'-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the "premutation" as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived ROS may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n=31, all FXTAS-free except 8), compared to age- and sex-matched controls (n=25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions, and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTAS-affected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals' scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by N-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome- and/or carrier-specifics. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset.


Neurodegenerative disorders; antioxidants; free radicals; metabolism; mitochondria; neurobiology; neurodegeneratio; neurodegeneration; oxidative stress; personalized medicine; reactive oxygen species; triplet nucleotide disease

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