Investigating Genes and Pathways Associated With Longevity and Neurodegenerative Disease

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Project Summary Aging is the single largest risk factor in the development of neurodegenerative diseases. An interesting characteristic of this link between aging and neurodegeneration is that populations predisposed to long lifespan appear to be able to delay or avoid the development of neurodegenerative disease entirely. I hypothesize that genes which modulate longevity can also confer neuroprotection, and that those genes protective against neurodegenerative pathologies can also extend healthy brain function during the process of aging. In Aim 1, I will identify which genes implicated in lifespan extension also ameliorate neurodegenerative disease phenotypes. Utilizing a high-throughput robotic behavioral assay system in concert with the genetic tractability of the Drosophila model, the Botas lab has compiled a neuroprotective gene dataset of over 1200 genes that play protective roles in the neurons of Drosophila models of Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease. I have also leveraged data from gene perturbation studies in numerous model organisms documented in the literature to construct a network of evolutionarily-conserved lifespan extending genes. Human longevity data will be integrated into this network using published genome-wide association and centenarian variant data. I will overlay this network with data from our neuroprotective gene dataset to identify genes that both extend lifespan and ameliorate neurodegenerative disease phenotypes. Then, gene set enrichment tools will be used to characterize functional pathways in the network and to identify those related to neuroprotection. Using genes within these pathways, and genes directly interacting with known neuroprotective variants, I will then validate whether other longevity genes are neuroprotective in the context of disease. I will utilize Drosophila models of neurodegenerative diseases to characterize whether alteration of these genes in neurons improves disease-related phenotypes using a sensitive high-throughput neuronal performance assay system. In Aim 2, I will identify whether genes that are protective in disease contexts can improve neuronal and/or glial health during aging. First, I will utilize cross-sectional transcriptomic and proteomic time-series datasets from the brains of flies, mice, and humans to characterize expression changes in the brain that occur with age and disease conserved across evolution. Overlaying this data with our large database of neuroprotective genes, I will identify changes in the brain that may play a protective role in preserving brain health or increase risk of disease onset. I will then use our large-scale in vivo assay system to determine if manipulating the expression of genes associated with aging or neuroprotection against disease improve the function of glia or a specific neuronal subtype during aging. I will use pathway enrichment tools to determine potential mechanisms by which genes that improve neuronal/glial health with age function. When this study is complete, it will deepen our understanding of the biological link between longevity and resilience/resistance to neurodegeneration and provide a pathway to potential therapeutics that can protect the aging brain against disease.