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bioRxiv · 10.1101/2020.08.30.274050

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

Szinyakovics, J.·Kiss, A. E.·Keresztes, F.·Vellai, T.·Kovacs, T.
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Abstract

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.

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Szinyakovics, J., Kiss, A. E., Keresztes, F., Vellai, T., Kovacs, T.. 2020-08-31. Rab2 is a potent new target for enhancing autophagy in the treatment of Parkinson's disease. https://doi.org/10.1101/2020.08.30.274050

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