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

Macroautophagy (hereafter referred to as autophagy) is an important self-renewal process in our cells, whereby potentially harmful cellular components are encapsulated within a double-membrane autophagosome and subsequently fused with a lysosome for degradation by acidic hydrolases. 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, it has been proven that autophagic activity declines with age, so it is therefore particularly important to stimulate autophagy during the lifespan of post-mitotic cells, such as neurons, where cell division is not a possibility in order to replace dead cells. Our research group aims to find new autophagy activation sites to stimulate the efficiency of acidic degradation in neurons during ageing. One approach 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 study, 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 the Drosophila nervous 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 of CG42795 exerts an effect on autophagy, with the capacity to enhance the locomotor ability of animals and prolong lifespan. Furthermore, the human orthologue of this GAP, the TBC1D30 protein showed a conserved function in HeLa cells. Silencing TBC1D30 increased the number of active Rab2 protein and enhanced autophagic activity in human cells. Our findings suggest that studying GAPs could be a promising new field of focus for ageing researchers. Further analysis of CG42795 and TBC1D30 could lead to the development of potential autophagy activators.