Assessment of Metabolism and Circadian Rhythm in Frontotemporal Dementia Using a Drosophila melanogaster Animal Model

Abstract

Abstract The purpose of this behavioral study was to establish proofs of concept in metabolism and circadian rhythm in Frontotemporal Dementia (FTD) using a Drosophila melanogaster animal model that had been genetically modified using the UAS-GAL4 system to have an overexpression of the Chromosome 9 Open Reading Frame 72 protein (C9ORF72). FTD is a progressive neurodegenerative disease, resulting in degeneration of the frontal cortex and the temporal lobe regions of the brain. Currently, there is no cure or treatment for FTD patients (Yang et al., 2020). The hexanucleotide repeat expansion in C9ORF2 is the most common genetic cause of sporadic and familial FTD cases (Sha et al., 2012). It is hypothesized the expansion in C9ORF72 leads to synthesis of toxic dipeptide repeats which contribute further to FTD pathology (Freibaum & Taylor, 2017). Recent research has shown inhibition of serine and arginine rich splicing protein 1 (SRSF1) or impeding the interaction of SRSF1 with nuclear RNA Export Factor 1 abrogates translocation of C9ORF72 to the cytoplasm, leads to the synthesis of dipeptide repeats, and mitigates neurotoxicity in Drosophila melanogaster (Hautbergue et al., 2017). There are unanswered questions regarding the effect C9ORF72 has on behavior with respect to metabolism and circadian rhythm. Results from this study showed an alteration in circadian rhythm in pathological mutant Drosophila compared to non- pathological Drosophila melanogaster aged one day and maintained at 25 °C. This study also confirmed an altered circadian rhythm in pathological Drosophila compared to non- pathological Drosophila aged 2-3 days and maintained at 25 °C. There was no change in metabolism in the pathological or non-pathological Drosophila melanogaster that had been aged five days and 14 days respectively when Drosophila were maintained at 25 °C or 29 °C. Collectively, the data from the behavioral proofs of concept generated by this study provided valuable baseline data that future research may be based upon.