Saxton, Aleen, Gatlin, Rachel, Wheeler, Jeanna, Kraemer, Brian, Chickering, Kaili, Price, Kelsey
[
International Worm Meeting,
2019]
Tauopathies are neurodegenerative diseases which are characterized by aggregates of insoluble tau that form neurofibrillary tangles (NFTs). These include Alzheimer's disease, progressive supranuclear palsy, and frontotemporal lobar degeneration (FTLD), some cases of which are caused by mutations in MAPT, the gene encoding the tau protein. Tau primarily binds to and stabilizes microtubules. However, when tau is pathological it loses its affinity for microtubules, becomes hyperphosphorylated, and forms NFTs. Using a Caenorhabditis elegans model of tauopathy, our group previously performed a genome-wide RNA-mediated interference (RNAi) screen to identify modifier genes that enhance the human tau induced uncoordinated (Unc) phenotype. This screen identified 60 genes that when knocked down enhance the Unc phenotype produced by human tau. We have selected 41 of these genes to further analyze. Due to the enhancement of the tau phenotype by knockdown of these genes, we expect that by overexpressing them we may see an amelioration of the tau phenotype. By microinjecting pools of several of these genes at once into N2, we induced overexpression of the genes in C. elegans. We are currently crossing strains carrying these extrachromosomal arrays with a human tau expressing C. elegans line and evaluating the effects on the tau phenotype using radial locomotion and liquid thrashing assays. If an effect is observed, we will generate integrated transgenic lines overexpressing individual candidate genes and perform further testing to determine which of the genes may have caused the suppression. We hope that this work may reveal potential target genes in the search for tauopathy treatments.