Metabolic Dysregulation in FXTAS Pathogenesis

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Common features of FXTAS include progressive intention tremor, gait ataxia, Parkinsonism, and cognitive decline. The neuropathological hallmarks of FXTAS include ubiquitin-positive intranuclear inclusions throughout the brain and marked dropout of Purkinje neurons in the cerebellum. Currently, data support two non-mutually exclusive molecular pathogenesis mechanisms for FXTAS: 1) RNA gain-of-function, in which rCGG repeat- binding proteins (RBPs) become functionally limited through sequestration by lengthy rCGG repeats, and 2) Repeat-associated non-AUG (RAN) translation, whereby translation through the CGG (or antisense CCG) repeats leads to the production of toxic homo-polypeptides, such as FMRpolyG, which in turn interfere with a variety of cellular functions. Multiple mouse models have been developed to study these mechanisms. Much remains unknown regarding the metabolic alterations associated with FXTAS, especially in the brain, and the most affected region, the cerebellum. Our previous work identified the metabolic alterations associated with FXTAS pathogenesis using our FXTAS mouse model that expresses 90 CGG repeats in cerebellar Purkinje neurons and exhibits the key phenotypic features of FXTAS. By combining global metabolic profiling with a Drosophila genetic screen, we have found that the sphingolipid metabolic pathway can modulate rCGG repeat toxicity. A preliminary study of 5 FXTAS postmortem brains compared to age-matched controls also identified alterations in the sphingolipid pathway. Untargeted metabolomic analysis of plasma samples from men with symptoms of FXTAS identified significant alterations in the sphingolipid pathway compared to noncarrier men. In the proposed study, we will expand on these findings using additional FXTAS mouse models, Drosophila models, and human samples. First, we will compare the lipidomic profile of a mouse model that expresses 99 CGG repeats and the FMRpolyG protein to a mouse model that expresses the expanded repeat without expressing the FMRpolyG protein. In addition, we will test for amelioration of FXTAS pathogenesis in flies with a drug that targets β-glucocerebrosidase (GBA), a key enzyme in the sphingolipid pathway that we have found is able to modulate rCGG repeat toxicity. We will also investigate the profile in FXTAS patients using additional post mortem brain samples and plasma samples that have been collected on a longitudinally-studied cohort for FXTAS pathogenesis. Our proposed work investigating the metabolic changes in FXTAS will aid in the identification of biomarkers as well as in understanding the pathogenesis of disease