Antagonizing tau spreading in Alzheimer’s disease by PI4K2A-mediated lysosomal quality control

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

PROJECT SUMMARY/ABSTRACT (30 lines of text): This K01 proposal is from Dr. Xiaojun Tan, Research Assistant Professor in the Aging Institute at the University of Pittsburgh School of Medicine. Dr. Tan has extensive and diverse experience with in vitro studies related to aging including cellular stress response, autophagy, lipid signaling, and innate immunity. Dr. Tan is pursuing a career in aging research with a goal of establishing his own lab in three years studying core principles in aging and neurodegeneration and developing novel translational therapeutics for age-related diseases, especially neurodegenerative diseases. A K01 Award would be critical in providing Dr. Tan with protected time for additional training in neurobiology and in vivo studies as well as career development to ensure his transitioning into an independent aging investigator. The proposed research project is the study of a new lysosomal quality control pathway in neuronal tau spreading and Alzheimer’s disease (AD). Specifically, Dr. Tan discovered that lysosomal membrane permeabilization/damage (LMP) triggers robust lipid signaling on lysosomes which in turn mediates rapid lysosomal repair. This pathway is dependent on LMP-stimulated lysosomal recruitment of the lipid kinase PI4K2A (phosphatidylinositol 4-kinase type 2 alpha). Rapid lysosomal repair is expected to effectively suppress tau fibril spreading in AD, as endocytosed tau fibrils are known to invade the cytosol of recipient cells by triggering LMP. Thus, the hypothesis is that PI4K2A senses LMP induced by tau fibrils and activates rapid lysosomal repair to prevent tau fibril spreading by blocking its lysosomal escape. Two aims will be pursued: (1) investigate the mechanism by which PI4K2A senses neuronal lysosomal damage by internalized tau fibrils; (2) determine the in vitro and in vivo impact of the PI4K2A pathway on tau spreading and tauopathy using Pi4k2a brain-specific knockout mice. To accomplish the proposed research, Dr. Tan will carry out a comprehensive training plan including formal course work, seminars, conferences and hands-on training as well as the mentorship from three leading experts in aging research with Dr. Toren Finkel as the primary mentor and Dr. Stacey Rizzo and Dr. Ana Maria Cuervo as co-mentors. Dr. Finkel has significant experience in developing new mouse models. Dr. Rizzo is an expert of Alzheimer’s disease and translational research. Dr. Cuervo is an international leader studying cellular quality control in aging and neurodegeneration who will also provide advice on Dr. Tan’s career development and grant applications. The proposed research training will focus on three categories (1) knowledge in neuroscience and Alzheimer’s disease; (2) tissue isolation and primary cultures; (3) mouse model generation and phenotyping. The career development goals in the award period include (1) expanding Dr. Tan’s collaboration network, (2) building leadership and lab management skills, (3) additional learning about mentoring and teaching, and (4) improving grant writing and presentation skills. Successful completion of the proposed research and training plan will provide the knowledge and experience necessary to progress toward Dr. Tan’s career goal of becoming an independent aging investigator studying neuronal aging and AD.