Effect of expression of human mutant CHMP2B, an ESCRT-III component involved in frontotemporal dementia, on circadian rhythms in Drosophila

The Ahmad Lab studies the effects of mutations associated with neurodegenerative diseases, like frontotemporal dementia, on sleep-wake cycle, using fruit flies as a model system.

Project Summary

Characterization of the disease-causing mutations provides important insights about the incidence, progression, and therapy of neurodegenerative disorders. Mutations in the CHMP2B gene, an ESCRT-III (endosomal sorting complexes required for transport) component, are associated with a hereditary form of frontotemporal dementia (FTD), the second most common form of age-dependent dementia, and Amyotrpoic Lateral Sclerosis (ALS). ESCRTs mediate sorting of membrane proteins into multivesicular bodies (MVBs) on their way to lysosomes for degradation. MVBs are involved in the endosomal-lysosomal trafficking pathway that plays a critical role in the regulation of cell surface receptors and their signaling pathways. Mutant CHMP2B (CHMP2BIntron5) protein causes neurodegeneration by disrupting the MVB pathway in humans, mice, and Drosophila. Ectopic expression of CHMP2BIntron5 in Drosophila during early and late stages of eye development causes melanotic deposits and deformities due to misregulation of the Toll and Notch receptors and their signaling pathways, respectively. Therefore, CHMP2BIntron5 differentially affects receptor-signaling pathways in a cellular and developmental context-dependent manner. Interestingly, FTD and other neurodegenerative disorders are also associated with a disruption in the sleep/wake circadian cycle but the mechanism is not well understood. The overall goal of this study is to estabilsh and characterize a potential role of CHMP2BIntron5 in the misregulation of circadian rhythms. CHMP2BIntron5 will be ectopically expressed in Drosophila eye and circadian pacemaker neurons to examine the effect of this expression on the structural and functional components of the circadian clock. Circadian behavior will be analyzed by observing free running locomotor activity period using automated activity monitors. Perturbation of the circadian rhythm at the cellular and molecular level will be determined by examining the expression levels of circadian pacemaker genes using histological (Immunohistochemistry of brain sections) and biochemical (Western blotting and Quantitative PCR) methods. Further, pharmacological and genetic screens are planned to identify modulators of the CHMP2BIntron5-mediated circadian rhythm phenotype(s).

Relevance of Research

The analysis and characterization of the CHMP2BIntron5-mediated defects in daily biological clock will improve understanding of sleep-related defects in neurological disorders. Moreover, identification of genetic and pharmacological modulators of the biological clock defects will provide important insights and potentially identify novel targets for intervention of sleep/wake cycle defects in FTD and other related disorders.