Project Grant F30AG096887

DEFINING THE METABOLIC PERTURBATIONS DRIVING AGE-DEPENDENT ALPHA-SYNUCLEIN NEURODEGENERATION - PROJECT SUMMARY PARKINSON'S DISEASE (PD) AND DEMENTIA WITH LEWY BODIES (DLB) ARE NEURODEGENERATIVE DISEASES (NDS) LINKED TO AGING AND CHARACTERIZED BY THE ACCUMULATION OF MISFOLDED ALPHA-SYNUCLEIN (ASYN) PROTEIN IN THE BRAIN. EVIDENCE SUGGESTS THAT DIVERSE METABOLIC PERTURBATIONS, A HALLMARK OF BOTH AGING AND SYNUCLEINOPATHIES, MAY PLAY A CRITICAL ROLE IN DISEASE PATHOGENESIS. AS A SENSOR OF CELLULAR ENERGY AND MASTER REGULATOR OF CATABOLIC VERSUS ANABOLIC BALANCE, AMP-ACTIVATED PROTEIN KINASE (AMPK) ACTIVITY HAS BEEN IMPLICATED IN BOTH AGING AND NDS, WITH ITS DECLINE ASSOCIATED WITH BOTH SHORTENED LIFESPAN AND NEURODEGENERATION. DESPITE THESE WELL- VALIDATED LINES OF EVIDENCE, THE CELLULAR LOCUS OF METABOLIC PERTURBATIONS, WHETHER THEY BE A DECREASE IN AMPK ACTIVITY OR ALTERATIONS TO METABOLIC HOMEOSTASIS MORE BROADLY, REMAINS POORLY UNDERSTOOD. IT COULD BE THAT DYSREGULATED METABOLISM IN NEURONS EXERTS A CELL-AUTONOMOUS EFFECT ON NEURODEGENERATION. OR, IT COULD BE THAT GLIA, THE NON-NEURONAL CELLS OF THE BRAIN PARENCHYMA THAT PROVIDE CRITICAL METABOLIC SUPPORT FOR NEURONS AND HAVE BEEN IMPLICATED IN ND PATHOGENESIS, ARE THE LOCUS OF CRITICAL CHANGES TO METABOLISM THAT HAVE A KNOCK-ON EFFECT IN NEURONS. THIS PROJECT SEEKS TO CONTRIBUTE TO THE FIELD IN TWO WAYS: (1) IDENTIFICATION OF INDIVIDUAL METABOLIC PATHWAYS MEDIATING NEURODEGENERATION IN AGING AND SYNUCLEINOPATHY AND (2) IDENTIFICATION OF THE CELLULAR LOCUS OF THESE METABOLIC PERTURBATIONS. THE CENTRAL HYPOTHESIS IS THAT AGING AND ASYN AGGREGATION SYNERGISTICALLY PROMOTE NEURODEGENERATION VIA METABOLIC DISRUPTIONS, INCLUDING DIMINISHED AMPK SIGNALING, IN BOTH NEURONS AND GLIA. AIM 1 WILL LEVERAGE AN UNBIASED APPROACH TO IDENTIFY METABOLIC PATHWAYS DYSREGULATED IN AGING AND ASYN AGGREGATION IN NEURONS AND GLIA. AIM 2 WILL ELUCIDATE THE NEUROPROTECTIVE ROLE OF AMPK SIGNALING IN NEURONS AND GLIA IN THE CONTEXT OF AGING AND ASYN AGGREGATION. THIS RESEARCH WILL PROVIDE CRITICAL INSIGHT INTO THE METABOLIC DRIVERS OF NEURODEGENERATION IN AGING AND SYNUCLEINOPATHIES. ELUCIDATION OF THE CELLULAR LOCUS OF PERTURBED METABOLISM FURTHER HAS THE POTENTIAL TO IDENTIFY TRANSLATABLE THERAPEUTIC TARGETS TO MITIGATE NEURODEGENERATION IN PD, DLB, AND RELATED DISORDERS. FURTHERMORE, THIS APPLICATION PROPOSES A COMPREHENSIVE AND INTERDISCIPLINARY TRAINING PLAN WITHIN A PROMINENT ACADEMIC MEDICAL AND RESEARCH INSTITUTION THAT SEAMLESSLY INTEGRATES WITH THE RESEARCH PROPOSAL, PROVIDING ESSENTIAL TRAINING IN METABOLOMICS, DROSOPHILA GENETICS, AND MOLECULAR NEUROBIOLOGY TO SUPPORT THE CANDIDATE'S CAREER GOAL OF LEADING AN ACADEMIC TRANSLATIONAL NEUROSCIENCE LABORATORY AS A PHYSICIAN-SCIENTIST.