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CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome
- Source :
- Journal of Neurochemistry, 107(6), 1671-1682. Wiley-Blackwell Publishing Ltd
- Publication Year :
- 2008
-
Abstract
- The 5′untranslated region (UTR) of the FMR1 gene contains a CGG-repeat, which may become unstable upon transmission to the next generation. When repeat length exceeds 200, the FMR1 gene generally undergoes methylation-mediated transcriptional silencing. The subsequent absence of the gene product Fragile X Mental Retardation Protein (FMRP) causes the mental retardation seen in fragile X patients. A CGG-repeat length between 55 and 200 trinucleotides has been termed the premutation (PM). Predominantly elderly male PM carriers are at risk of developing a progressive neurodegenerative disorder: fragile X-associated tremor/ataxia syndrome (FXTAS). All PM carriers have elevated FMR1 mRNA levels, in spite of slightly decreased FMRP levels. The presence of intranuclear ubiquitin-positive inclusions in many brain regions is a neuropathological hallmark of FXTAS. Studies in humans attempting to correlate neuropathological outcomes with molecular measures are difficult because of the limited availability of tissue. Therefore, we have used the expanded CGG-repeat knock-in mouse model of FXTAS to examine the relationship between the molecular and neuropathological parameters in brain. We present Fmr1 mRNA and Fmrp levels and the presence of intranuclear inclusions at different repeat lengths. Contrary to existing hypotheses, our results suggest that inclusion formation may not depend on the elevation per se of Fmr1 transcript levels in aged CGG mice.
- Subjects :
- Untranslated region
Male
congenital, hereditary, and neonatal diseases and abnormalities
Ataxia
Intranuclear Inclusion Bodies
Biology
Biochemistry
Article
Gene product
Cellular and Molecular Neuroscience
Fragile X Mental Retardation Protein
Mice
medicine
Gene silencing
Animals
RNA, Messenger
Genetics
Cerebral Cortex
Age Factors
medicine.disease
FMR1
nervous system diseases
Fragile X syndrome
Disease Models, Animal
Fragile X Syndrome
medicine.symptom
Trinucleotide repeat expansion
Trinucleotide Repeat Expansion
Fragile X-associated tremor/ataxia syndrome
Subjects
Details
- Language :
- English
- ISSN :
- 00223042
- Database :
- OpenAIRE
- Journal :
- Journal of Neurochemistry, 107(6), 1671-1682. Wiley-Blackwell Publishing Ltd
- Accession number :
- edsair.doi.dedup.....2bf4858fa75ca135238ec866406712f6