Abstract
An intronic hexanucleotide (GGGGCC) expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In the decade following its discovery, much progress has been made in enhancing our understanding of how it precipitates disease. Both loss of function caused by reduced C9orf72 transcript levels, and gain of function mechanisms, triggered by the production of repetitive sense and antisense RNA and dipeptide repeat proteins, are thought to contribute to the toxicity. Drosophila models, with their unrivaled genetic tractability and short lifespan, have played a key role in developing our understanding of C9orf72-related FTD/ALS. There is no C9orf72 homolog in fly, and although this precludes investigations into loss of function toxicity, it is useful for elucidating mechanisms underpinning gain of function toxicity. To date there are a range of Drosophila C9orf72 models, encompassing different aspects of gain of function toxicity. In addition to pure repeat transgenes, which produce both repeat RNA and dipeptide repeat proteins (DPRs), RNA only models and DPR models have been generated to unpick the individual contributions of RNA and each dipeptide repeat protein to C9orf72 toxicity. In this review, we discuss how Drosophila models have shaped our understanding of C9orf72 gain of function toxicity, and address opportunities to utilize these models for further research.
Highlights
The Frontotemporal Dementia and Amyotrophic Lateral Sclerosis SpectrumFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two progressive diseases of the nervous system which display significant neuropathological, genetic and clinical overlap
In this review we focus on the contributions Drosophila melanogaster models have made to our understanding of chromosome 9 open reading frame 72 (C9orf72)-related frontotemporal dementia (FTD) and ALS
Both models implicated GR in TDP-43 dysfunction and demonstrated that GR expression caused significant cytoplasmic mislocalisation of TBPH, GR did not directly colocalize with it. This suggestion of a causal link between GR and TDP-43 pathology supports a recent report regarding C9orf72-ALS cases which demonstrated that the presence of GR inclusions correlated with both TDP-43 accumulation and neurodegeneration (Saberi et al, 2018). This data is important in understanding how TDP-43 pathology is consistently observed in C9orf72-FTD/ALS patients, in the absence of RNA foci or dipeptide repeat proteins (DPRs) inclusions
Summary
The Frontotemporal Dementia and Amyotrophic Lateral Sclerosis SpectrumFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two progressive diseases of the nervous system which display significant neuropathological, genetic and clinical overlap. Since the initial identification of C9orf72 hexanucleotide expansion mutations as the most common genetic cause of both FTD and ALS, a number of in vitro and in vivo models have been established in order to elucidate the molecular mechanism underpinning disease.
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