TY - JOUR
T1 - Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome
AU - Ross-Inta, Catherine
AU - Omanska-Klusek, Alicja
AU - Wong, Sarah
AU - Barrow, Cedrick
AU - Garcia-Arocena, Dolores
AU - Iwahashi, Christine
AU - Berry-Kravis, Elizabeth
AU - Hagerman, Randi J
AU - Hagerman, Paul J
AU - Giulivi, Cecilia R
PY - 2010/8/1
Y1 - 2010/8/1
N2 - FXTAS (fragile X-associated tremor/ataxia syndrome) is a lateonset 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 andwithout 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 premutationwho 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.MDin 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.
AB - FXTAS (fragile X-associated tremor/ataxia syndrome) is a lateonset 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 andwithout 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 premutationwho 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.MDin 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.
KW - Fragile X-associated tremor/ataxia syndrome (FXTAS)
KW - Mitochondrion
KW - Neurodegeneration
KW - Oxidative stress
KW - Trinucleotide repeat expansion
KW - Unfolded protein response
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U2 - 10.1042/BJ20091960
DO - 10.1042/BJ20091960
M3 - Article
C2 - 20513237
AN - SCOPUS:77955071201
VL - 429
SP - 545
EP - 552
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 3
ER -