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Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

Authors
  • West, Ryan J. H.1, 2
  • Sharpe, Joanne L.3
  • Voelzmann, André3
  • Munro, Anna L.3
  • Hahn, Ines3
  • Baines, Richard A.3
  • Pickering-Brown, Stuart3
  • 1 University of Sheffield, 385 Glossop Road, Sheffield, S10 2HQ, UK , Sheffield (United Kingdom)
  • 2 University of Sheffield, Sheffield, S10 2TN, UK , Sheffield (United Kingdom)
  • 3 The University of Manchester, Manchester, UK , Manchester (United Kingdom)
Type
Published Article
Journal
Acta Neuropathologica Communications
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Sep 07, 2020
Volume
8
Issue
1
Identifiers
DOI: 10.1186/s40478-020-01028-y
Source
Springer Nature
Keywords
License
Green

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.

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