The goal is to establish critical developmental ages and molecular targets for treating pathology in Fragile X premutation carriers (PM) and in Fragile X-associated tremor/ataxia (FXTAS) using CGG knock-in mice (CGGex KI) and doxycycline-inducible dox-CGG99 mice. The Fragile X gene (FMR1) is polymorphic for the number of CGG trinucleotide repeats in the 5'-untranslated region. Repeat sizes in the general population range between 5-55 CGG repeats. In Fragile X syndrome (FXS) repeat expansions exceed 200, silencing expression of FMR1 and its protein product FMRP, resulting in mental retardation. Carriers of the FMR1 PM have between 55-200 repeats and were originally thought to be free of pathology. However, several neurological disorders occur in carriers of the PM, including anxiety, depression and mild motor and cognitive impairments. The incidence of the PM in the general population is high, with estimates of 1:250 for females and 1:800 for males, or more than 1.5 million PM carriers in the United States alone. Approximately 40% of male and 8-11% of female PM carriers are also at risk for developing FXTAS, a late onset neurodegenerative disorder causing tremor, ataxia, brain pathology, cognitive loss, dementia and early death in some individuals. Therefore, there is a need to define critical ages when pathology begins, developmental windows when the disorder may be halted or reversed, and the cellular and molecular mechanisms that can be used as therapeutic targets for symptomatic PM carriers and patients with FXTAS. To address these important questions we have developed powerful in vivo and in vitro mouse models of PM and FXTAS, including dox-inducible mice in which expression of a CGG99 repeat expansion can be activated by doxycycline (dox) and then inactivated following dox withdrawal. These mice will be used to establish critical developmental periods when disease processes begin and developmental periods when disease might be halted or reversed. We will also establish whether pathology in astrocytes, neurons or both is necessary and sufficient to cause disease. Finally, we will use these mouse models to test novel treatment strategies using gapmer antisense oligonucleotides (AONs) that may improve neurological function in symptomatic carriers of the PM and in patients with FXTAS.
This project will study Fragile Associated tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder that causes cognitive decline, and may be one of the most common causes of tremor/ataxia in older adults. The project is significant for public health because the numbers of FXTAS patients requiring medical care will be increasing significantly as the population ages. The goal is to establish when during development the disease process begins, and if disease progression can be halted or reversed and neurological function improved by appropriate treatments.
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