Title: CGG repeat associated translation in Fragile X-associated Tremor/Ataxia Syndrome. Abstract: Dominantly inherited nucleotide repeat expansion disorders are thought to elicit neurodegeneration in one of two ways: 1) The repeat as RNA can bind to and sequester specific proteins, preventing them from performing their normal functions;or 2) If the repeat is translated into protein, the repetitive amino acid expansion can trigger toxicity through a variety of mechanisms including protein misfolding and aggregation. Traditionally, the dominant contribution of each pathogenic mechanism has been suggested by the repeat's location within the disease gene, with exonic repeats exerting toxicity primarily as protein and non-exonic repeats presumably acting via RNA-mediated mechanisms. Recent data, however, indicate that repeats in """"""""non-coding"""""""" regions of transcripts can be aberrantly translated into proteins through Repeat Associated Non- AUG initiated (RAN) translation. In light of this new finding, defining the relative contributions of RNA- and protein-mediated toxic processes in each repeat expansion disorder has surfaced as a critical issue in the field. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an inherited neurodegenerative disorder that results from a CGG repeat expansion at the beginning of the fragile X gene, FMR1. It is characterized pathologically by the formation of proteinaceous inclusions in the brains of patients. Work to date suggests that the repeat is toxic as RNA, but our group recently showed that the CGG repeat expansion also elicits RAN translation (""""""""CGG RAN translation"""""""") to produce an aggregation-prone, homopolymeric polyglycine containing protein. This protein aggregates in model systems and is present in inclusions in FXTAS disease brain. In this proposal, we will determine whether the CGG repeat in FXTAS triggers neurodegeneration as RNA, as a toxic protein, or both, and then interrogate how this newly discovered RAN translation occurs mechanistically. To address these questions, we will utilize new fly models of FXTAS to determine the relative abilities of CGG repeats as RNA and as RAN translated proteins to elicit neurodegeneration. We will then extend these findings to pathological and behavioral assessments of two knock-in mouse models of FXTAS that differ in their ability to support CGG RAN translation. In parallel, we will employ a series of biochemical and cell-based approaches to explore the mechanisms underlying CGG RAN translation. These studies should provide critical insight into FXTAS pathogenesis while offering a relevant case-study for other repeat expansion disorders, and in the process facilitate the identification of proximal therapeutic targets based on improved understanding of disease mechanisms.

Public Health Relevance

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) is a progressive degenerative disease of the brain that results from a genetic mutation. This research project addresses the surprising finding that this mutation triggers production of a toxic protein whose existence was not previously recognized. We will explore how this toxic protein contributes to FXTAS symptoms and work to understand what factors regulate its production, with a long term goal of developing novel therapies for patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Riddle, Robert D
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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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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