Characterising the Function of the Novel Endosomal protein Tmep in D.melanogaster

Frontotemporal dementia (FTD) is a neurodegenerative disease affecting the frontal and temporal lobes. One genetic locus associated with FTD is the ESCRT-III protein CHMP2B. The CHMP2BIntron5 mutation can cause FTD and induces defects in vesicular trafficking in both mammalian and Drosophila melanogaster systems, leading to neuronal dysfunction. To identify genetic enhancers and suppressors of a CHMP2BIntron5 associated phenotype, we utilised an eye screen in D.melanogaster, and identified loss- and gain-of-function in the CG12004 gene as a modifier. CG12004 encodes a conserved protein that colocalises with endosomal markers in a mouse model. We named this 7TM protein Transmembrane Endosomal Protein (Tmep). The loss of the Tmep ortholog TMEM184B accelerates axon degeneration after injury in mice. However, the mechanism behind the TMEM184B role in nervous system function remains elusive. To determine the function of Tmep, we used D.melanogaster as our model system. We show that Tmep is widely expressed in motor neurons, muscle, the fat body and the digestion organs. In motor neurons, Tmep localises in lysosomal compartments, and the absence of Tmep leads to an increase in endosomal compartments and a decrease in late endosomal/lysosomal compartments. In adults and larvae, Tmep is required for normal locomotion. Tmep female larvae exhibit more branched synapses, bouton defects, and greater active zone density, suggesting deficits in synaptic transmission and sexual dimorphism in Tmep function. Tmep animals show starvation resistance during development, have defective lipid content and aberrant fat body morphology. Our study demonstrates the vital role of Tmep in neuronal function and development.