Mapping tauopathy-induced changes in subcellular proteostasis with compartment-targeted sensors - PROJECT SUMMARY. Decline in proteostasis is a defining feature of cellular aging and of age-related diseases. Recent studies have shown that protein quality control in each organelle is impacted by organelle-specific challenges but also interconnected with proteostasis in other cell compartments. Depending on the context, this organelle interdependence has been proposed to preserve or derange protein quality control. However, the investigation of subcellular proteostasis has been limited by the lack of suitable transgenic reporters for monitoring protein quality control in multiple cell compartments in vivo. Alzheimer’s disease (AD) is defined by the action of aggregation-prone pathogenic proteins that perturb proteostasis. Despite a confined subcellular localization, these pathogenic proteins impact the function of multiple organelles and compartments across the cell. However, the role of inter-organelle crosstalk in AD remains largely unexplored. Specifically, it remains unknown whether perturbation of proteostasis in a specific cell compartment by an AD-linked pathogenic protein reverberates on protein quality control in other compartments. In our preliminary studies, we have generated transgenic compartment-targeted misfolding-prone proteins that, depending on the experimental design, can be used as sensors of subcellular proteostasis or as tools to offset proteostasis. By using these novel probes, we have found that aging differentially affects proteostasis in the nucleus, endoplasmic reticulum, mitochondria, and cytoplasm. On this basis, we now propose to determine how AD pathogenic proteins affect protein quality control in distinct subcellular compartments and, conversely, how compartment-restricted derangement of proteostasis impacts AD. For these studies, we will examine microtubule-associated protein tau (MAPT) mutants that have been linked to the onset of an AD-related condition (frontotemporal dementia) in humans. Specifically, we propose to determine whether tauopathy modulates proteostasis in distinct cell compartments; how aging synergizes with AD-related pathogenic tau in regulating subcellular proteostasis; and whether, conversely, protein misfolding in distinct subcellular compartments differentially impacts tauopathy. Altogether, these studies promise to provide fundamental understanding on how mutant tau cross-regulates subcellular proteostasis, which may be relevant for understanding how organelle and cell function are deranged in AD.
