Project Grant F30NS149794

DISSECTING NEURONAL MOLECULAR TRAJECTORIES AND GLIAL RESPONSES TO A-SYNUCLEIN AGGREGATES IN LEWY BODY DISEASES - ABSTRACT LEWY BODY DISEASES (LBDS) INCLUDING PARKINSON'S DISEASE (PD), PARKINSON'S DISEASE DEMENTIA (PDD), AND DEMENTIA WITH LEWY BODIES (DLB) ARE PROGRESSIVE NEUROLOGICAL DISEASES CHARACTERIZED BY THE ACCUMULATION OF MISFOLDED A-SYNUCLEIN (TERMED LEWY PATHOLOGY). CLINICALLY, THESE DISEASES ARE DISTINGUISHED BY THE INITIAL SYMPTOM ONSET, MOTOR DYSFUNCTION IN PD AND PDD AND COGNITIVE IMPAIRMENT IN DLB. AT PRESENT TREATMENT ONLY TEMPORARILY MITIGATES SYMPTOMS AS NO DISEASE MODIFYING TREATMENT EXISTS. THIS WORK SEEKS TO REFRAME A- SYNUCLEIN INCLUSIONS NOT AS ENDPOINTS, BUT AS PART OF A MOLECULAR TRAJECTORY THAT CAN BE MAPPED ACROSS TIME AND SPACE USING SINGLE-CELL SPATIAL TRANSCRIPTOMICS. THIS TRAINING IS INTENDED TO 1) PROVIDE LEADERSHIP AND MENTORSHIP SKILLS NECESSARY TO BE AN INDEPENDENT INVESTIGATOR 2) ADVANCE TECHNICAL PROFICIENCY IN BIOINFORMATICS AND PRIMARY NEURON CULTURE TO CONTRIBUTE AND ACCELERATE THE PROGRESS OF MY FIELD, 3) ENHANCE SCIENTIFIC COMMUNICATION TO EFFECTIVELY SHARE MY WORK, AND 4) ADVANCE CLINICAL SKILLS NECESSARY TO TRANSITION TO RESIDENCY AS A COMPETENT AND CARING PHYSICIAN. PREVIOUS WORK IN MY LAB HAS SHOWN A MOLECULAR SIGNATURE OF LEWY-BODY BEARING NEURONS (LAMDA), THAT REVEALS COORDINATED DOWNREGULATION OF MITOCHONDRIAL, UBIQUITIN-PROTEOSOME, ENDO-LYSOMAL, CYTOSKELETAL PATHWAYS, ALONG WITH UPREGULATION OF DNA REPAIR AND COMPLEMENT/CYTOKINE PATHWAYS. THESE BULK ANALYSES OBSCURE THE POTENTIAL MEANINGFUL HETEROGENEITY BETWEEN SINGLE-CELLS INCLUDING WHETHER FEATURES ARE CELL-TYPE SPECIFIC, HOW THIS FEATURE CHANGES OVER TIME, AND NEURON-GLIA INTERACTIONS. I HYPOTHESIZE THAT A-SYNUCLEIN AGGREGATION INITIATES A CELL-TYPE SPECIFIC MOLECULAR TRAJECTORY THAT CULMINATES IN NEURONAL DYSFUNCTION AND DEATH. EXPANDING ON THE PREVIOUS WORK, I WILL UTILIZE SINGLE-CELL SPATIAL TRANSCRIPTOMICS OF HUMAN CINGULATE GYRUS TO DEFINE THE MOLECULAR TRAJECTORY OF NEURONS WITH LEWY BODIES AND THE LOCAL GLIAL RESPONSE TO A-SYNUCLEIN AGGREGATES (AIM 1). IN ADDITION, AS PART OF THE LAMDA SIGNATURE OUR LAB IDENTIFIED 25 UPREGULATED KINASES, TO UNDERSTAND THEIR IMPACT ON PATHOLOGY AND NEURONAL HEALTH I WILL PERFORM A LIMITED KNOCKDOWN SCREEN (AIM 2). TOGETHER, THESE STUDIES WILL DEFINE THE MOLECULAR TRAJECTORY OF NEURONS WITH LEWY PATHOLOGY, CLARIFY THE ROLE OF GLIAL INTERACTIONS, AND FUNCTIONALLY TEST MECHANISMS DRIVING A-SYNUCLEIN-MEDIATED NEURODEGENERATION. THIS WORK AIMS TO PROVIDE A FOUNDATION FOR THE DESIGN OF DISEASE-MODIFYING THERAPIES FOR LBDS. THIS PROJECT WILL BE PERFORMED IN THE HIGHLY COLLABORATIVE, WELL-RESOURCED ENVIRONMENT OF VAN ANDEL INSTITUTE AND MICHIGAN STATE COLLEGE OF HUMAN MEDICINE THAT INTEGRATES CLINICAL AND RESEARCH EXPERTISE. IN ADDITION TO ADVANCING THE FIELD, THESE STUDIES WILL PROVIDE ME WITH CRITICAL EXPERTISE IN SINGLE-CELL SPATIAL TRANSCRIPTOMICS, NEURODEGENERATION MODELS, AND NEURONAL-GLIAL INTERACTIONS, TRAINING THAT WILL DIRECTLY INFORM MY DEVELOPMENT AS A PHYSICIAN-SCIENTIST IN NEUROLOGY AND MOVEMENT DISORDERS.