Author(s): Megan L. Mair, Baylor College of Medicine; Emma McCormick, Baylor College of Medicine; Bismark Amoh, Baylor College of Medicine; Cole Deisseroth, Baylor College of Medicine; Jiayang Li, Baylor College of Medicine; Justin Moore, Baylor College of Medicine; Juan Botas, Baylor College of Medicine //

ABSTRACT: Research objectives: Aging is the single largest risk factor for the development of neurodegenerative disease. An interesting feature 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. The objective of this study is to systemically analyze which neurodegenerative disease modifiers also have an impact on lifespan and healthspan of the central nervous system by using bioinformatics techniques and the Drosophila melanogaster animal model.    Methods: Utilizing a unique, high-throughput robotic behavioral assay system in tandem with the genetic tractability of the Drosophila animal model, our lab has identified over 1,000 genes that act as modifiers in Drosophila models of Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease when expression is manipulated in neurons and/or glia by the GAL4-UAS system. In addition, we have leveraged data from gene perturbation studies in model organisms documented in GeneAge and the literature in order to construct a biological network of lifespan extending genes that are conserved across evolution. Utilizing these methodologies to select gene candidates, we have screened genetic variants for their ability to protect against neurodegenerative disease pathology and confer longevity in Drosophila disease and aging models. Additionally, we have screened these disease modifiers for their ability to extend healthspan in the neurons and glia of healthy, non-diseased flies by using longitudinal behavioral assays.     Results: By overlaying data from our neurodegenerative disease modifier screens with our cross-species network of lifespan extension genes, we have identified genetic variants that both extend lifespan and act as suppressors of neurodegenerative disease phenotypes. We have identified 30 Drosophila genetic variants that are both disease suppressors and are known to extend lifespan. Of these, 14 were found to act as a suppressor in more than one disease model (i.e., suppress disease-related phenotypes in both AD and HD models). In addition, we found that 238 genes, or approximately 20% of the nodes found in the network of lifespan extension genes, are orthologs of a Drosophila neurodegenerative disease modifier.     Preliminary results from our longitudinal behavioral assays suggest that when knocked down in neurons and glia, several genetic variants that are neurodegenerative disease modifiers can also delay or otherwise diminish the age-related behavioral phenotype observed in disease-free aging flies.     Conclusions: Using our unique modifier dataset, Drosophila assay system, and bioinformatics tools, we have characterized a pool of genetic variants that are neurodegenerative disease modifiers and confer longevity. Further, we have identified disease modifiers that improve CNS healthspan in disease-free aging flies. The analyses conducted in this research will help us better understand the genetic link between long lifespan and protection against neurodegenerative disease, and could help in the development of new therapies that improve brain health with age.

Source of Funding: NIH/NIA R01 AG057339