Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome
Autor: | Cedrick Barrow, Catherine Ross-Inta, Randi J Hagerman, Alicja Omanska-Klusek, Sarah Wong, Paul J. Hagerman, Christine Iwahashi, Dolores Garcia-Arocena, Cecilia R Giulivi, Elizabeth Berry-Kravis |
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Rok vydání: | 2010 |
Předmět: |
Adult
congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Ataxia Mitochondrion Biology Biochemistry Article Electron Transport Fragile X Mental Retardation Protein Adenosine Triphosphate Internal medicine Tremor medicine Humans Allele Molecular Biology Aged Aged 80 and over Genetics Neurodegeneration Cell Biology Middle Aged medicine.disease FMR1 Mitochondria Fragile X syndrome Endocrinology Fragile X Syndrome Protein Biosynthesis Mutation medicine.symptom Trinucleotide repeat expansion Fragile X-associated tremor/ataxia syndrome |
Zdroj: | Biochemical Journal. 429:545-552 |
ISSN: | 1470-8728 0264-6021 |
Popis: | 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. |
Databáze: | OpenAIRE |
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