The GTPase-activating protein CG42795 is a potent neuronal regulator of ageing inDrosophila melanogaster

Abstract

Macroautophagy (hereafter autophagy) is the process by which cellular components to be degraded are isolated from the cytoplasm by a double membrane (the mature vesicle, called the autophagosome). Its contents are degraded by acid hydrolases after fusion with the lysosome. This lysosomal degradation process is essential for maintaining cellular homeostasis. Dysfunctional autophagy can lead to the accumulation of cytotoxic protein forms that contribute to the onset of age-related diseases. However, autophagy activity declines as we age/throughout life. Stimulating its function during lifespan is particularly important in post-mitotic cells such as neurons, where cells cannot divide to replace the dead cells. Our research group aims to find new autophagy activation sites to stimulate the efficiency of acid degradation in neurons during ageing. One possibility is the stimulation of membrane fusion events, which are necessary for autophagic degradation, through the activation of small GTPase enzymes. Our previous results have shown that neuron-specific overexpression of the activated form of the Rab2 small GTPase has autophagy and lifespan-enhancing effects. In the present experiment, we used an RNA interference screen to investigate whether silencing 12 GTPase-activating proteins (GAPs) belonging to the TBC1 domain family can enhance Rab2 activation in theDrosophilanervous system. Several of the GAPs studied increased the number of Rab2-positive structures, 5 of which were selected for further screening. Our results suggest that neuronal silencing ofCG42795has autophagy-enhancing effects, the ability to improve the locomotor ability of animals, and prolong lifespan. Our research has shown that the study of GAPs could be a promising new avenue of research for ageing researchers. Further analysis of CG42795 could lead to the development of potential autophagy activators.