A common feature of Alzheimer?s disease (AD), as well as other older age onset neurodegenerative diseases, is the accumulation of misfolded, abnormally modified proteins. In AD, aggregates of tau are a classical hallmark. A significant contributing factor to the formation of these proteinaceous accumulations is dysfunction of the lysosome-dependent degradative pathways. Interestingly, the majority of autosomal dominant familial AD (FAD) cases are caused by mutations in presenilin 1 (PS1), the catalytic subunit of the ? secretase complex, which also likely facilitates lysosomal function. However, the role of PS1 in mediating lysosome biology and the clearance of tau has not been fully delineated. Given previous studies and our preliminary data, the UNDERLYING PREMISE of this proposal is that in neurons PS1 plays a fundamental role in regulating the function of lysosomes and, thus, tau turnover. Lysosomes play a key role in maintaining proteostasis as multiple degradative pathways direct their cargos to the lysosome for degradation/recycling. Alterations in the activity or intracellular localization of lysosomes contribute to the pathogenic processes of these neurodegenerative diseases. Given the importance of lysosome function to neuron health, understanding how PS1 impacts lysosome biology is of high importance. CRITICAL KNOWLEDGE GAPS include: how depletion of PS1 in primary neurons impacts lysosome pH, the effects of PS1 depletion on autophagosome-lysosome and endosome-lysosome fusion, the impact of PS1 depletion on tau turnover and how re-acidification of lysosomes in neurons with PS1 depleted affects the PS1-induced lysosomal fusion defects and deficiencies in tau turnover. Considering these critical knowledge gaps the OVERALL HYPOTHESIS is that depletion of PS1 leads to impairment of lysosome function, localization and fusion events, which negatively impact tau clearance. In the context of this overall hypothesis, the specific aims of this proposal are to test the hypotheses: (1) that PS1 plays a role in the acidification, activity, and localization of lysosomes and other degradative vesicles within different neuronal compartments and (2) that vesicle- mediated processing/clearance and intraneuronal localization of tau is impaired by knockdown of PS1. These studies will be carried out using primary rat cortical neuron cultures. Overall this a transformative project that addresses significant gaps in our scientific knowledge. The proposal is innovative in conceptualizing PS1 as a key regulator of lysosome function and thus a significant contributor to proteostasis in general and tau more specifically. Further, technically it is innovative as we will be using an optogenetically driven proton pump to decrease the pH of lysosomes after PS1 knockdown to determine if maintaining an acidified lysosome is sufficient to restore its function. The IMPACT of these studies will be a significant contribution to our understanding of the role of PS1 in regulating tau biology via lysosomal function, thus informing general perspectives of neurobiological degeneration in aging. .
Presenilin 1 (PS1) is the protein that is mutated in the majority of familial Alzheimer?s disease cases and is the catalytic subunit of the ?-secretase complex that is necessary for the production of A?. Recent studies have suggested that PS1 also plays key roles in lysosome biology. Given the importance of lysosomes in maintaining proteostasis, the studies in this proposal on the role of PS1 in mediating lysosome function in neurons are of fundamental importance.
