Objectives: Fragile X associated Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder characterized by dementia, gait disorder and tremor. It results from an expanded CGG nucleotide repeat in the Fragile X Mental Retardation gene, FMR1. This repeat expansion interferes with translation of the Fragile X protein, FMRP, such that it's basal and activity-dependent expression is lower in patients and in animal models. There is emerging evidence that FMRP dysfunction may also contribute to other neurodegenerative disorders such as Alzheimer's disease. Our application addresses the critical question of whether FMRP insufficiency plays a meaningful role in FXTAS pathogenesis. To begin addressing this question, we evaluated whether neuronal dysfunction was present in a mouse model of FXTAS. We reasoned that the CGG repeat would block production of FMRP at synapses, leading to defects in synaptic plasticity that could contribute to the clinical phenotype in patients. Our preliminary results demonstrate alterations in synaptic plasticity in FXTAS model mice that mirror changes seen in mouse models of Fragile X Syndrome (FXS) that completely lack FMRP. These changes in synaptic electrophysiology are mechanistically distinct and correlate with a decrease in both basal and activity dependent expression of FMRP. These preliminary findings lead to our central hypothesis that translational inefficiency of expanded CGG repeat FMR1 mRNA contributes to neuronal dysfunction and clinical disease in FXTAS. The central objective of the proposed experiments is to define the mechanisms by which this neuronal dysfunction occurs in FXTAS model mice, with a long-term objective of developing novel therapeutic targets for Veterans with FXTAS and other neurodegenerative conditions. Research Plan/Methods: To address our central hypothesis, we will utilize a combination of molecular, cellular and electrophysiological techniques in which our labs already have established expertise. We will first determine the mechanistic features by which mGluR dependent long term depression is altered in cultured neurons and hippocampal slices from CGG-KI and FMR1 KO mice. To potentially translate these findings toward therapeutic development, we will take advantage of established work in models of FXS, where FMRP expression is completely lost. In these systems, antagonists to type I mGluRs alleviate many aspects of the phenotype seen in animal models. Phase II and III trials are ongoing in FXS with these drugs. Thus, we will test the potential efficacy of mGluR antagonists in a model of FXTAS using established behavioral assays known to be abnormal in FXTAS mice or patients. Clinical Relevance: The long term objective of this work is rational therapeutic development for patients with FXTAS and other degenerative disorders such as Alzheimer's disease where FMRP may play a role in disease pathogenesis. The proposed experiments should define an important role for FMRP dysfunction in FXTAS and potentially in other neurodegenerative disorders. These studies also provide pre-clinical testing of a promising therapeutic agent already in clinical trials, thus offering the promise of rapid clinical translation. In sum, the proposed experiments are novel, feasible and of high significance to both FXTAS and more common neurodegenerative disorders such as Alzheimer's disease
Neurodegenerative disorders cause death and disability in VA patients, yet treatments remain limited. The current proposal focuses on treating neuronal dysfunction that precedes frank degeneration as it may be more amenable to therapy. Although the proposal centers on one cause of neurodegeneration, FXTAS, the overall approach and the therapeutic target, the synaptic protein FMRP, have broad applicability to other neurodegenerative disorders, including Alzheimer's disease. Our preliminary evidence supports the hypothesis that FMRP insufficiency contributes to disease symptoms in FXTAS and tests whether targeting this insufficiency is a valid therapeutic strategy. FXTAS is an under-recognized health problem in veterans. We see the debilitating impact of this condition in our clinic. As 1 in 3000 men will develop FXTAS as they age, it will likely impact the health of a substantial portion of the veteran population. Take together, the proposed studies are timely, novel, feasible, and important to the health care priorities of VA patients today.
| Krans, Amy; Kearse, Michael G; Todd, Peter K (2016) Repeat-associated non-AUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome. Ann Neurol 80:871-881 |
| Green, Katelyn M; Linsalata, Alexander E; Todd, Peter K (2016) RAN translation-What makes it run? Brain Res 1647:30-42 |
| Kearse, Michael G; Green, Katelyn M; Krans, Amy et al. (2016) CGG Repeat-Associated Non-AUG Translation Utilizes a Cap-Dependent Scanning Mechanism of Initiation to Produce Toxic Proteins. Mol Cell 62:314-322 |
| Renoux, Abigail J; Carducci, Nicholas M; Ahmady, Arya A et al. (2014) Fragile X mental retardation protein expression in Alzheimer's disease. Front Genet 5:360 |
| Renoux, A J; Sala-Hamrick, K J; Carducci, N M et al. (2014) Impaired sensorimotor gating in Fmr1 knock out and Fragile X premutation model mice. Behav Brain Res 267:42-5 |
| Iliff, Adam J; Renoux, Abigail J; Krans, Amy et al. (2013) Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice. Hum Mol Genet 22:1180-92 |
| Renoux, Abigail J; Todd, Peter K (2012) Neurodegeneration the RNA way. Prog Neurobiol 97:173-89 |
