Biology subjects

Keresztes, F.

Publications and source records attributed to Keresztes, F..

3 recordsLinked to original sources

bioRxiv2025

Comparative analysis of two autophagy-enhancing small molecules (AUTEN-67 and -99) in a Drosophila model of Spinocerebellar ataxia type 1

Autophagy is a lysosome-mediated self-degradation process of eukaryotic cells which is critical for the elimination of cellular damage. Its capacity progressively declines with age, and this change can lead to the development of various neurodegenerative pathologies including Spinocerebellar ataxia type 1 (SCA1). SCA1 is mainly caused by mutations in the polyglutamine region of Ataxin 1 protein. In patients affected by the disease, Purkinje neurons of the cerebellum frequently undergo demise and eventually become lost. Here we tested whether two well-characterized autophagy-enhancing small molecules, AUTEN-67 and -99, which antagonize the autophagy complex Vps34 through blocking the myotubularin-related lipid phosphatase MTMR14/EDTP, have the capacity to ameliorate SCA1 symptoms. We found that in a Drosophila model of SCA1, only AUTEN-67 exerts positive effects including improvement of climbing ability and extending life span. Based on these results, we hypothesized that the two compounds influence autophagy in the brain in a neuron-specific manner. Indeed, according to data we obtained, AUTEN-67 and -99 exhibit shared and unique functional domains in the Drosophila brain. AUTENs enhanced autophagy in GABAergic and dopaminergic neurons. In addition, AUTEN-67 also affected autophagy in cholinergic neurons, while AUTEN-99 triggered the process in glutaminergic neurons and motoneurons. We also observed varying efficiencies between the two AUTENs among different subtypes of cultured hippocampal neurons of mice. These data suggest that the two compounds display neuron-specific differences in exerting autophagy-enhancing effects, and may lead to a better understanding of in which types of neurons autophagy could potentially be activated to treat SCA1 in human patients.

cell biology↗

bioRxiv2024

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.

genetics↗

bioRxiv2020

Rab2 is a potent new target for enhancing autophagy in the treatment of Parkinson's disease

Macroautophagy is a lysosomal-dependent degradational pathway of eukaryotic cells, during which toxic, unnecessary, and damaged intracellular components are broken down. Autophagic activity declines with age, and this change could contribute to the accumulation of intracellular damage at advanced ages, causing cells to lose their functionality and vitality. This could be particularly problematic in post-mitotic cells include neurons, the mass destruction of which leads to different neurodegenerative diseases. We aim to discover new regulation points where autophagy could be specifically activated, and test these potential drug targets in Drosophila neurodegenerative disease models. One possible way to activate autophagy is through the enhancement of autophagosome-lysosome fusion to become autolysosome. This fusion is regulated by HOPS (homotypic fusion and protein sorting) and SNARE (Snap receptor) complexes. The HOPS complex forms a bridge between lysosome and autophagosome with the assistance of small GTPase Rab (Ras-associated binding) proteins. Thus, Rab proteins are essential for autolysosome maturation, and among Rab proteins, Rab2 is required for the degradation of autophagic cargo. Our results revealed that GTP-locked (constitutively active) Rab2 (Rab2 CA) expression reduces the levels of the autophagic substrate p62/Ref2P in dopaminergic neurons, and improved the climbing ability of animals during aging. The expression of Rab2 CA also increased lifespan in a Parkinsons disease model (human mutant alpha-synuclein [A53T] overexpressed animals). In these animals, Rab2 CA expression significantly increased autophagic degradation as compared to control. These results may reveal a new, more specific drug target for autophagic activation treating todays incurable neurodegenerative diseases.

genetics↗