REGULATION OF PROTEOSTASIS AND TAUOPATHY BY MALTOSE-INDUCED SIGNALING

PROJECT SUMMARY Proper signaling is necessary for homeostasis in multicellular organisms. Once considered mere byproducts of cellular metabolism, small metabolites have now emerged as an important class of signaling factors that regulate tissue and whole-body functions. However, the role of small metabolites in proteostasis and age-related neurodegeneration is largely unexplored. We have recently found that the disaccharide maltose and the maltose- producing amylase enzyme Amyrel preserve proteostasis of the central nervous system (CNS) during aging in Drosophila. Specifically, Amyrel and maltose protect from tauopathy and prevent the age-related accumulation of poly-ubiquitinated proteins in the brain and retina during aging via the transcriptional induction of chaperones. Conversely, knockdown of SLC45 maltose transporters reduces the expression of Amyrel-induced chaperones and worsens brain proteostasis and tauopathy. Moreover, maltose preserves proteostasis and neuronal activity in human brain organoids challenged by thermal stress. Altogether, these findings indicate that maltose is a novel, conserved regulator of CNS proteostasis. However, the mechanisms via which maltose preserves proteostasis are incompletely understood and it remains unexplored how maltose impacts proteostasis across cell compartments. Specifically, although maltose is a chemical chaperone, many small metabolites are now known to act as signaling factors. This raises the question on whether maltose regulates proteostasis via signaling mechanisms independent from its chemical chaperone activity. In agreement with this hypothesis, our preliminary studies now identify the transcription factor Broad as a possible mediator of maltose-induced chaperone expression and CNS proteostasis during aging. On this basis, we propose the following aims: to determine the mechanisms via which Amyrel/SLC45 protects from neurodegeneration and functional decline induced by pathogenic tau/MAPT (aim 1); to determine the impact of Amyrel/SLC45 on proteostasis in different subcellular compartments (aim 2); and to determine whether Amyrel/SLC45 signaling regulates CNS proteostasis and tauopathy via the transcription factor Broad (aim 3). Altogether, these studies promise to provide fundamental understanding of a novel maltose-induced signaling pathway that preserves brain proteostasis during aging and that protects from tauopathy. Knowledge gained from these studies will guide the design of effective therapies to preserve and/or reinstate proteostasis in patients with tauopathies and Alzheimer’s disease.