Project Summary/Abstract The decline in cognitive function is a debilitating hallmark of both aging and age-associated neurodegenerative diseases, including Alzheimer?s and Parkinson?s. As the population ages, the prevalence of these disorders is rapidly increasing, yet no disease-modifying therapies exist. Further research is necessary to understand the underlying disease mechanisms and the relationship to aging. We have identified branched-chain amino acid transferase 1 (bcat-1), which catalyzes the first step in branched-chain amino acid (BCAA) metabolism, as a novel gene linked to Parkinson?s disease. BCAA metabolism is implicated in cognitive impairment in several diseases, including Alzheimer?s, Down?s syndrome with Alzheimer?s, traumatic brain injury, and maple syrup urine disease. However, the mechanisms by which BCAA metabolism and bcat-1 affect cognition remain unexplored. We are using the well-established aging model system, C. elegans, to answer this fundamental biological question, given its complex set of cognitive abilities, highly evolutionarily-conserved molecular machinery, and vast array of genetic tools available for its manipulation. We have found that downregulating neuronal bcat-1 in C. elegans recapitulates many features of Parkinson?s disease, including motor dysfunction and neurodegeneration, and this proposal will evaluate cognitive function. Paradoxically, reducing bcat-1 or increasing BCAAs lengthens lifespan in yeast, worms, and mice. These findings suggest that bcat-1 may mediate opposing effects on longevity and neuronal health. The proposed study aims to investigate this relationship, using associative learning and memory assays developed in our lab. mTOR signaling is required for bcat-1-dependent lifespan extension in C. elegans, and BCAA metabolism affects mitochondrial function through mTOR-dependent and independent pathways. Thus, the specific role of mTOR in bcat-1 regulation of longevity and learning & memory will be defined, with an emphasis on mitochondrial signaling. Mitochondrial function and metabolism will also be tested in worms with bcat-1-dependent lifespan and cognitive phenotypes. The results of this work will suggest new targets for treatment strategies and interventions in an effort to promote longevity while maintaining or even enhancing cognitive ability. The proposed research plan will provide the applicant with expert-level training in two powerful, complementary approaches: tissue-specific transcriptomics, and high-resolution metabolomics. The training in these techniques and the proposed individualized mentorship plan will provide the applicant with the skills and preparation necessary to pursue an independent academic career in the fields of aging and age-related neurodegenerative disease.
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