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

Abstract

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 reactive oxygen species (ROS) may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n = 31, all FXTAS-free except 8), compared with 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 FXTASaffected 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 carrierspecific. 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. online address: http://www.molmed.org

Microglial cell activation and senescence are characteristic of the pathology FXTAS

“…In addition, inflammation is supported by the lipid profile as well as the increase in oxidative stress–mediated damage to carbohydrates and proteins in serum of FXTAS patients . Fibroblasts from premutation individuals also show increased mitochondrial reactive oxygen species production accompanied by increased mtDNA deletions and increased biomarkers of lipid and protein oxidative–nitrative damage . Overall, these data indicate the presence of an inflammatory state in the FXTAS brain.…”

Fragile X-Associated Neuropsychiatric Disorders (FXAND)

“…The extensive molecular pathology and mitochondrial studies that have been carried out in premutation carriers has led to a wealth of molecular information to link to the psychiatric problems that carriers experience ( 11 , 12 , 32 , 33 ). We know that psychiatric problems (usually depression and/or anxiety) occur before the neurological problems develop in those with FXTAS ( 34 , 35 ).…”

Repeat-associated non-AUG (RAN) translation and other molecular mechanisms in Fragile X Tremor Ataxia Syndrome

“…First, mitochondrial dysfunction (e.g. decreases in ATP production, oxygen uptake, and mitochondrial protein expression) and elevated levels of reactive oxygen species (ROS) have been reported in both cell and animal models of FXTAS as well as in fibroblasts and brain tissue of premutation carriers ( Ross-Inta et al, 2010 , Napoli et al, 2011 , Napoli et al, 2016 Oct , Kaplan et al, 2012 , Hukema et al, 2014 , Song et al, 2016 , Alvarez-Mora et al, 2016 , Giulivi et al, 2016 , Robin et al, 2017 Apr 21 ). Second, other studies support a model whereby transcribed CGG repeat expansions create R-loops, (i.e.…”