期刊
HUMAN MOLECULAR GENETICS
卷 20, 期 15, 页码 3079-3092出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr211
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资金
- Neuropharm
- Roche
- Johnson Johnson
- Novartis
- Seaside therapeutics
- Curemark
- Forest pharmaceuticals
- Autism Speaks Foundation [58739]
- National Institute on Aging [AG024488]
- National Institutes of Health Interdisciplinary Research Consortium (IRC) [RL1 AG032119, UL1 DE19583, RL1 AG032115]
- Spastic Paralysis and Allied Diseases of the Central Nervous System Research Foundation of The Illinois-Eastern Iowa District Kiwanis International
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects individuals who are carriers of small CGG premutation expansions in the fragile X mental retardation 1 (FMR1) gene. Mitochondrial dysfunction was observed as an incipient pathological process occurring in individuals who do not display overt features of FXTAS (1). Fibroblasts from premutation carriers had lower oxidative phosphorylation capacity (35% of controls) and Complex IV activity (45%), and higher precursor-to-mature ratios (P: M) of nDNA-encoded mitochondrial proteins (3.1-fold). However, fibroblasts from carriers with FXTAS symptoms presented higher FMR1 mRNA expression (3-fold) and lower Complex V (38%) and aconitase activities (43%). Higher P: M of ATPase beta-subunit (ATPB) and frataxin were also observed in cortex from patients that died with FXTAS symptoms. Biochemical findings observed in FXTAS cells (lower mature frataxin, lower Complex IV and aconitase activities) along with common phenotypic traits shared by Friedreich's ataxia and FXTAS carriers (e. g. gait ataxia, loss of coordination) are consistent with a defective iron homeostasis in both diseases. Higher P: M, and lower ZnT6 and mature frataxin protein expression suggested defective zinc and iron metabolism arising from altered ZnT protein expression, which in turn impairs the activity of mitochondrial Zn-dependent proteases, critical for the import and processing of cytosolic precursors, such as frataxin. In support of this hypothesis, Zn-treated fibroblasts showed a significant recovery of ATPB P: M, ATPase activity and doubling time, whereas Zn and desferrioxamine extended these recoveries and rescued Complex IV activity.
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