Fragile X-associated tremor/Ataxia syndrome (FXTAS) is one of a large class of human neurological disorders that result from instability and expansion of nucleotide repeats. In FXTAS, a CGG nucleotide repeat expands in the 5? untranslated region of the fragile X gene, FMR1, and triggers formation of aggregated protein inclusions in the patient brains. Our group found that the FXTAS CGG repeat gets translated into toxic homopolymeric proteins despite its location outside of a canonical open reading frame through a process known as repeat associated Non-AUG initiated (RAN) translation. RAN translated proteins accumulate in patient tissues and contribute to CGG repeat associated toxicity in multiple model systems. In this proposal, we will explore how this alternative translational initiation occurs mechanistically. Our preliminary data suggests that RAN translation at CGG repeats is selectively enhanced by cellular stress, which typically blocks protein synthesis. In parallel, CGG repeats directly elicit cellular stress and trigger stress granule formation. Our central hypothesis is that CGG RAN translation and cellular stress participate in a feed-forward loop that drives neurodegeneration. Our collaborative team will directly test this hypothesis by using biochemical techniques as well as drosophila, mouse and human induced pluripotent stem cell models of FXTAS.
In Aim 1 we will determine how cellular stress selectively activates RAN translation, focusing specifically on initiation factors that underlie this process.
In Aim 2, we will elucidate how CGG repeats elicit cellular stress and influence stress granule dynamics and whether interventions in this process impact repeat toxicity.
In Aim 3, we will test whether selective blockade of cellular stress pathways can disrupt this feed forward loop and alleviate CGG repeat associated toxicity across disease models. Together, these studies will illuminate critical events in the pathogenesis of FXTAS and other nucleotide repeat expansion disorders while rigorously testing two complementary & innovative approaches to selective RAN translation blockade.

Public Health Relevance

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) is a progressive degenerative disease of the brain that results from a repeat expansion mutation that triggers production of a toxic protein. We will explore how this toxic protein is made, how its production contributes to FXTAS relevant symptoms in model systems and how we might block its production. Our long term goal is to leverage these findings to develop novel therapies for FXTAS patients and patients with other repeat expansions that cause neurodegeneration.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Riddle, Robert D
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Glineburg, M Rebecca; Todd, Peter K; Charlet-Berguerand, Nicolas et al. (2018) Repeat-associated non-AUG (RAN) translation and other molecular mechanisms in Fragile X Tremor Ataxia Syndrome. Brain Res 1693:43-54
Green, Katelyn M; Glineburg, M Rebecca; Kearse, Michael G et al. (2017) RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat Commun 8:2005
Sellier, Chantal; Buijsen, Ronald A M; He, Fang et al. (2017) Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome. Neuron 93:331-347
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
Yang, Wang-Yong; He, Fang; Strack, Rita L et al. (2016) Small Molecule Recognition and Tools to Study Modulation of r(CGG)(exp) in Fragile X-Associated Tremor Ataxia Syndrome. ACS Chem Biol 11:2456-65
Chun, Sang Y; Rodriguez, Caitlin M; Todd, Peter K et al. (2016) SPECtre: a spectral coherence--based classifier of actively translated transcripts from ribosome profiling sequence data. BMC Bioinformatics 17:482
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
Oh, Seok Yoon; He, Fang; Krans, Amy et al. (2015) RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome. Hum Mol Genet 24:4317-26
Kearse, Michael G; Todd, Peter K (2014) Repeat-associated non-AUG translation and its impact in neurodegenerative disease. Neurotherapeutics 11:721-31

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