ENDOSOMAL MICROAUTOPHAGY IN DROSOPHILA

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PARENT AWARD Summary: Endosomal Microautophagy in Drosophila Caring for an ever aging society represents an increasing socio-economic burden and continuing efforts are required to improve healthspan. Critically, aging is a major ‘risk factor’ for devastating diseases including cancer, immune and cardiovascular diseases, as well as dementias due to neurodegeneration, all of which are strongly affected by a decline in proteostasis. Damaged or altered cytosolic proteins are cleared by the proteasome and autophagy. Importantly, autophagy has the additional role of providing nutrients to cells under stress conditions such as starvation, and is thus essential for energy balance. The removal of damaged organelles and aggregated proteins is thus essential to protect the nervous system, the liver and kidneys against age related disorders. Macroautophagy (MA), chaperone mediated autophagy (CMA) and endosomal microautophagy (eMI) are the three major forms of autophagy. MA engulfs bulk-regions of cytoplasm including organelles in a double membrane vesicle (autophagosome). Autophagosome fusion with lysosomes leads to the degradation of the engulfed material. CMA and eMI mostly degrade proteins containing a targeting motif (KFERQ related sequences) that is recognized by the cytoplasmic Hsc70. We have established a genetic system to study eMI in Drosophila, overcoming a significant hurdle preventing the characterization of the physiological role of eMI, which previously had only been characterized biochemically and by EM in mammals. Hence, we can exploit the genetic power of Drosophila to assess the role of this most recent variant of autophagy. Using our system, we will determine the physiological function and regulation of eMI. In particular, we will identify biological processes controlled by eMI. Furthermore, we will address how kinases we have identified as candidate regulators alter eMI, with a focus on Drosophila models of human neurodegenerative diseases.