Role of selective autophagy in aging and neurodegeneration: a small molecule approach - PROJECT SUMMARY/ABSTRACT A hypothesis of aging is that the accumulation of cellular damage can lead to tissue malfunction and organismal deterioration. A key mechanism for maintaining cellular homeostasis and preserving cell function is autophagy, a hydrolytic cellular recycling process whereby cytosolic materials, referred to as cargo, including lipid droplets (LDs) and damaged proteins, are degraded in the lysosome. In turn, aberrations in autophagy can result in the accumulation of different toxic cytosolic contents, which is a molecular signature of many age-related disorders, including neurodegeneration. While there is a prominent functional link between autophagy, aging and diseases, the molecular mechanisms that cause the age-dependent decreases in autophagy remain unclear. Notably, autophagy can also selectively recruit one type of molecule for degradation. Recent studies support the hypothesis that selective autophagy plays a crucial role in combating chronic diseases. Several human brain post-mortem studies have uncovered lipid species that accumulate in brains affected by Alzheimer’s disease (AD), possibly impeding neuronal function and thereby contributing to neurodegeneration. Therefore, discovering different interventions that can be used to affect lipophagy (LD turnover) selectively may be ideal for tackling lipidotoxicity-linked AD. However, such pharmacological or genetic tools are currently unavailable. Furthermore, selective cellular factors that can facilitate LD recruitment for lipophagy remain unknown. In this proposal, I aim to address these greater needs in understanding the regulatory mechanisms of lipophagy and its function relevant to aging and neurodegenerative disorders. Our lab recently performed a cellular LD clearance high-throughput screen to identify small molecules and pathways that induce selective lipid clearing autophagy for slowing age-related diseases. Among these, we identified compound A20 that clears lipids in an autophagy-dependent manner in the nematode C. elegans to promote healthspan and lifespan. Emerging evidence suggests that A20 may act via lipophagy to clear lipids. I hypothesize that uncovering the lipophagy mechanism utilized by A20 will help us identify novel lipophagy regulators. Furthermore, since lipid accumulation is now linked to AD, I will employ a novel human AD patient- derived organoid model (3D neuronal culture with astrocytes) to determine whether A20 normalizes the lipid- linked pathogenic signature and normalizes pathogenic molecular phenotypes. Finally, I will characterize the functional changes in lipophagy and lipid homeostasis during AD using these human-derived organoid models. My studies are significant, as they will help us generate new mechanistic insights towards lipophagy activation during aging linked to AD. Such knowledge is vital to further our understanding of diseases exhibiting a lipophagy deregulation component. Furthermore, completion of these studies may potentially reveal strategies that could be used to combat neurodegenerative diseases.
