期刊
NEURODEGENERATIVE DISEASES
卷 17, 期 1, 页码 22-30出版社
KARGER
DOI: 10.1159/000446803
关键词
Fragile X-associated tremor/ataxia syndrome; Fragile X mental retardation 1 premutation; Cellular biomarkers; Mitochondrial respiration; Blood lymphoblasts; White matter hyperintensities
资金
- National Institutes of Child Health and Human Development [R01 HD 36071]
- La Trobe University Department of Microbiology
- School of Life Sciences
- 'Understanding Disease' Research Focus Area
Background: The need for accessible cellular biomarkers of neurodegeneration in carriers of the fragile X mental retardation 1 (FMR1) premutation (PM) alleles. Objective: To assess the mitochondrial status and respiration in blood lymphoblasts from PM carriers manifesting the fragile X-associated tremor/ataxia syndrome (FXTAS) and non-FXTAS carriers, and their relationship with the brain white matter lesions. Methods: Oxygen consumption rates (OCR) and ATP synthesis using a Seahorse XF(e)24 Extracellular Flux Analyser, and steady-state parameters of mitochondrial function were assessed in cultured lymphoblasts from 16 PM males (including 11 FXTAS patients) and 9 matched controls. The regional white matter hyperintensity (WMH) scores were obtained from MRI. Results: Mitochondrial respiratory activity was significantly elevated in lymphoblasts from PM carriers compared with controls, with a 2- to 3-fold increase in basal and maximum OCR attributable to complex I activity, and ATP synthesis, accompanied by unaltered mitochondrial mass and membrane potential. The changes, which were more advanced in FXTAS patients, were significantly associated with the WMH scores in the supratentorial regions. Conclusion: The dramatic increase in mitochondrial activity in lymphoblasts from PM carriers may represent either the early stages of disease (specific alterations in short-lived blood cells) or an activation of the lymphocytes under pathological situations. These changes may provide early, convenient blood biomarkers of clinical involvements. (C) 2016 S. Karger AG, Basel
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