Glysocaminoglycan Modifications as Regulators of Alzheimer's Disease-Related Pathologies

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Project Summary/Abstract As described by the High Priority Research Topics for this RFA, there is compelling evidence that glycosylation plays “critical roles in the early pathogenesis and progression of AD” yet the “potential of these molecules to serve as biomarkers and targets of disease intervention remains largely unexplored”. Specific areas of program relevance included the “role of extracellular matrix and proteoglycans in … accumulation of AD-related pathologies”. These areas are topics my laboratory has recently explored and my group has been involved in establishing the biological functions of heparan sulfate modified proteins over the last 20 years. In recent work we have shown that heparan sulfate proteoglycans regulate membrane trafficking, including autophagy, endocytosis and mitochondrial surveillance(1), processes central to neurodegenerative pathology. We have shown that modest changes in heparan sulfate structure, such as sulfation state or chain length, can increase catabolic membrane trafficking, including delivery of autophagosomes to the lysosome. These findings suggest that changing heparan sulfate structure could counteract the cellular processes that are compromised in AD and related pathologies. This hypothesis is supported by our demonstration that partial reductions in specific heparan sulfate modifying enzyme encoding genes can suppress cell loss in three distinct Drosophila models of neurodegenerative diseases(2) including AD. It is important to point out that the level of these changes do not disrupt developmental patterning but actually confers increased lifespan and resistance to oxidative stress. Using a panel of CRISPR-generated mutant human cell lines affecting heparan sulfate biosynthesis we have shown that the regulation of membrane trafficking by these molecules is conserved in human cells. We now wish to extend these observations into medically relevant models of AD to determine if heparan sulfate biosynthesis is a viable therapeutic target for AD and related pathologies. These studies employ both iPSC-derived neurons bearing mutations in known AD susceptibility genes (presenilin and APP), and a Drosophila model of age-dependent neurodegeneration, where conditional knockdown of presenilin function is achieved in adult neurons. In both of these systems we propose to determine if changes in heparan sulfate biosynthesis achieved by targeted knockdown of key biosynthetic enzyme encoding genes can achieve rescue of cellular phenotypes, and reverse the alterations in autophagy, mitophagy, and membrane trafficking that have been observed in human tissues as well as iPSC-derived neurons from patients.