Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a progressive neurodegenerative disease characterized by tremor with ataxia, brain atrophy and cognitive defects. FXTAS is caused by CGG expansions, varying in the length from ~55 to 200 repeats (CGG55-200), in the 5' UTR of the FMR1 gene. The CGG expansions more than 200 repeats in the same gene cause the Fragile X Syndrome (FXS), an intellectual disability, distinct from FXTAS. Long CGG expansions silence the transcription of the FMR1 gene; while short expansions elevate the transcription of the FMR1. Numerous models show that the FMR1 mRNA with CGG55-200 repeats or RNA CGG55-200 repeats outside of the FMR1 mRNA cause neurodegeneration. The main pathologic feature of FXTAS is the formation of the ubiquitin (Ub)-positive inclusions that contain the proteasome and several RNA-binding proteins. However, the role of the Ub- proteasome system and RNA-binding proteins in the FXTAS pathology is not understood. The primary targets of the RNA CGG repeats also remain unknown. Previous work in my lab was focused on the mechanisms for Myotonic Dystrophies type 1 and type 2 which are caused by RNA CUG and CCUG repeats. In the course of these studies, we have found that CUG and CCUG repeats alter RNA metabolism by interaction with different RNA-binding proteins and by formation of soluble and precipitated RNA-protein complexes (RPCs). CUG and CCUG RNAs form soluble complexes with RNA-binding protein, CUGBP1, increasing CUGBP1 stability. CCUG repeats also affect protein degradation via formation of large RPCs, containing the proteasome and stress-related proteins. We propose that, similar to DM, short (55-200) RNA CGG repeats form soluble and precipitated RPCs. We suggest that soluble rCGG-RPCs might contain RNA-binding proteins such as CUGBP1, Pur? and hnRNP A2/B1, affecting their function. In support of this hypothesis, we have found that CUGBP1 is increased in brains of FMR1-CGG98 knock in mice. It is known that the precipitated rCGG repeats (foci) bind Sam68, MBNL1 and hnRNP G. We suggest that the excessive binding of these proteins to the precipitated RPCs may attract the proteasome leading to the Ub-positive inclusions. The main hypothesis of this application is that the brain atrophy and neurodegeneration in FXTAS is due to: (1) misregulation of RNA processing by RNA-binding proteins bound in soluble and precipitated RPCs; and (2) due to altered protein degradation. To determine the role of these toxic events in the FXTAS pathology, we propose to identify the primary targets of the rCGG100 and the FMR1-CGG90 RNAs using a tet-regulated cell model (Aim 1). The role of elevation of CUGBP1 in the neurodegeneration in vivo will be determined in rCGG90 transgenic and FMR1-CGG98 knock in mice of different age (Aim 2). These studies will help to identify the molecular mechanism of FXTAS and will provide a background for the development of therapy for FXTAS.

Public Health Relevance

The Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a progressive neurological disease affecting elderly patients that carry the CGG expansions in the pre-mutation range in the gene for Fragile X syndrome. There is no cure for this disease. While the current evidence suggests the toxic role of the RNA CGG repeats; the molecular mechanisms by which the rCGG repeats cause brain atrophy and neuro-degeneration in FXTAS are not known. We propose to apply basic science expertise to delineate the mechanism of brain atrophy and neurodegeneration in FXTAS. This work will provide a basis for the development of the therapy for FXTAS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Riddle, Robert D
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Cincinnati Children's Hospital Medical Center
United States
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