The GTPase-activating protein CG42795 is a potent neuronal regulator of ageing in D rosophila 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 autophagy 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 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 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. 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.