Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome - PubMed (original) (raw)

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

Catherine Ross-Inta et al. Biochem J. 2010.

Abstract

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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Figures

Figure 1. Mitochondrial protein expression and nitrotyrosine content in ATPB in cultured primary dermal fibroblasts from control, premutation carriers and FXTAS patients

Changes in ATPB (A), MnSOD (B), CCO IV (C) and nitrotyrosine in ATPB (D) as a function of CGG repeat length in fibroblasts from premutation carriers with (F) or without (P) FXTAS symptoms, or controls (C; controls with <40 CGG repeats). All results are expressed as the percentage of mean control values. All samples from Table 1 were tested for these parameters and those excluded were due to limited sample amount, lack of linear response between protein loading and ECL response, or because they were not different from controls. Actin was used as a loading control.

Figure 2. Mitochondrial protein expression in frontal brain cortex from controls and FXTAS patients

Changes in ATPB (A) and MnSOD (B) as a function of CGG repeat length in fibroblasts from premutation carriers with (F) or without (P) FXTAS symptoms, or controls (C; controls with <40 CGG repeats). All samples from Table 4 were tested for these parameters and those excluded were due to limited sample amount, lack of linear response between protein loading and ECL response, or because they were not different from controls. All results are expressed as the percentage of mean control values. VDAC1 was used as a loading control.

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Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome - PubMed (original) (raw)