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

Ryan J H West,Richard A Baines,André Voelzmann,Stuart Pickering-Brown,Joanne L Sharpe,Ines Hahn,Anna L Munro

doi:10.1186/s40478-020-01028-y

Ryan J H West, Richard A Baines + Show 5 more

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https://doi.org/10.1186/s40478-020-01028-y

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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.

Highlights

Frontotemporal dementia (FTD) is a common form of early-onset dementia
West et al acta neuropathol commun (2020) 8:158 the hexanucleotide expansion leads to haploinsufficiency of the C9orf72 gene, 2/transcription of the expansion leads to the formation of toxic RNA foci and 3/non-canonical, non-AUG translation of repeat RNA leads to the formation of toxic dipeptide repeat proteins (DPRs) (Poly-glycine alanine (GA), Poly-alanine proline (AP), Poly-proline arginine (PR), Poly-glycine arginine (GR) and Poly-GP)
While it is possible that all three of these mechanisms contribute towards disease, studies have shown that C9orf72 knockout models fail to recapitulate FTD or motor neuron disease (MND) phenotypes, suggesting that even though haploinsufficiency may potentiate toxic RNA and DPR gain-of-function it is unlikely to precipitate the disease in its own right [4, 10]

Summary

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, The molecular mechanisms of neurodegeneration associated with the C9orf hexanucleotide expansion have yet to be fully elucidated. While it is possible that all three of these mechanisms contribute towards disease, studies have shown that C9orf knockout models fail to recapitulate FTD or MND phenotypes, suggesting that even though haploinsufficiency may potentiate toxic RNA and DPR gain-of-function it is unlikely to precipitate the disease in its own right [4, 10]. The contribution of each gain-of-function hypothesis has yet to be fully determined a number of crucial studies have demonstrated that DPRs may be the most significant driver of neurodegeneration [17, 30, 32]

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