A Drosophila Model of Frontotemporal Dementia (FTD) Based on C9ORF72 Hexanucleotide Repeat Expansion

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by a spectrum of symptoms such as loss of intellectual functions, including memory problems, impaired reasoning, abstract thinking, executive function, that can severely impact daily living activities. Frontotemporal lobar degeneration (FTDL) leads to a diverse group of conditions that are hallmarked by atrophy in the prefrontal and anterior temporal cortices. FTD is substantially less common than Alzheimer’s disease, but still greatly impacts individual lives leading to high socioeconomic costs to treat. This specialized level of care is valued at $244 billion, but its costs extend to the family caregivers’ who have an increased risk for emotional distress and negative physical and mental outcomes. Additionally, the overall incidence of cases of FTD is expected to increase, as our aging population is expected to grow by 2030 to include 1 in 5 Americans 65 years old and over. Approximately, 43% of FTD patients have a family history related to dementia or associated neurodegenerative diseases, with up to 27% of individuals carrying an autosomal dominant mutation. When examining the subsets of familial FTD cases, mutations in three genes, microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72, are prominent. The overarching hypothesis for this project is that overexpression of C9orf72 hexanucleotide repeat expansions (HREs) in RNA and/or dipeptide repeats (DPRs) in the encoded proteins in mushroom body neurons cause FTD like phenotypes in Drosophila. The present findings in this study show that overexpression of C9orf72 hexanucleotide repeat expansions (HREs) and DPRs in Drosophila MBs causes FTD like phenotypes. Sleep studies revealed that young flies expressing RNA only HREs exhibited greater sleepiness, while polyGR DPR flies displayed sleep changes later in their lifespan. Old (60 day) RNA only HRE expressing males showed sleep fragmentation while female flies exhibited greater sleepiness. Y-Maze assays uncovered that both RNA only HREs and polyGR DPRs caused increased locomotion rather than working memory deficits, as expected. This finding indicates possible hyperactivity in C9orf72 hexanucleotide repeat expansion flies through an increase in movement at both young and old age points. Morphological studies showed a profound, age dependent axonal thinning. In summary, this study shows that both C9orf72 HRE and DPR expressing flies exhibit sleep dysregulation, hyperactivity, and MB lobe thinning changes that could be examined closer to determine the underlying mechanisms of disease and provide further information on the genetic pathways and cellular mechanisms behind C9orf72 induced FTD.