Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotyp
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RESEARCH
Co‑expression of C9orf72 related dipeptide‑repeats over 1000 repeat units reveals age‑ and combination‑specific phenotypic profiles in Drosophila Ryan J. H. West1,2*† , Joanne L. Sharpe3†, André Voelzmann4, Anna L. Munro3, Ines Hahn4, Richard A. Baines3 and Stuart Pickering‑Brown3*
Abstract A large intronic hexanucleotide repeat expansion (GGGGCC) within the C9orf72 (C9orf72-SMCR8 Complex Subunit) locus is the most prevalent genetic cause of both Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND). In patients this expansion is typically hundreds to thousands of repeat units in length. Repeat associated non-AUG translation of the expansion leads to the formation of toxic, pathological Dipeptide-Repeat Proteins (DPRs). To date there remains a lack of in vivo models expressing C9orf72 related DPRs with a repeat length of more than a few hundred repeats. As such our understanding of how physiologically relevant repeat length DPRs effect the nervous system in an ageing in vivo system remains limited. In this study we generated Drosophila models expressing DPRs over 1000 repeat units in length, a known pathological length in humans. Using these models, we demonstrate each DPR exhibits a unique, age-dependent, phenotypic and pathological profile. Furthermore, we show co-expression of specific DPR combinations leads to distinct, age-dependent, phenotypes not observed through expression of single DPRs. We propose these models represent a unique, in vivo, tool for dissecting the molecular mechanisms implicated in disease pathology, opening up new avenues in the study of both MND and FTD. Keywords: Drosophila, Frontotemporal dementia, FTD, MND, Dipeptide-repeats, C9orf72, ALS Introduction Frontotemporal dementia (FTD) is a common form of early-onset dementia. It is clinically and pathologically heterogeneous and can co-occur with motor neuron disease (MND). It has a strong genetic association with up to 40% of patients presenting with a family history of disease [25]. The most prevalent genetic cause of FTD, *Correspondence: [email protected]; [email protected] † Ryan J. H. West and Joanne L. Sharpe contributed equally 1 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385 Glossop Road, Sheffield S10 2HQ, UK 3 Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK Full list of author information is available at the end of the article
identified to date, is an intronic hexanucleotide repeat expansion (GGG GCC ) within the C9orf72 (C9orf72SMCR8 Complex Subunit) locus [23]. In patients this expansion is typically greater than 500, and commonly thousands of, repeats in length. In unaffected individuals there are usually fewer than 25 repeats [1, 5, 31]. This mutation has also been identified as a common cause of MND, leading to the view that FTD and MND represent a clinical and pathological spectrum of a single disease [6]. The molecular mechanisms of neurodege
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