Discovering genetic regulators of pathological tau accumulation using a fluorescent C. elegans model of tauopathy

Abstract

Tauopathies comprise a group of aging-related neurodegenerative diseases that are pathologically characterized by aggregation of the microtubule-associated protein tau. Transgenic Caenorhabditis elegans serve as a powerful model organism to study tauopathy disease mechanisms, but moderating transgenic expression level has proven problematic. We generated a suite of transgenic strains with varying expression levels of photoconvertible Dendra2::tau. These strains exhibited expression level-dependent neuronal dysfunction that was modifiable by known genetic suppressors or an enhancer of tauopathy. Optical pulse-chase experiments reveal that Dendra2::tau turnover rate depends on Dendra2::tau expression level but not co-expression with the known tau enhancer TDP-43. Through a forward genetic screen using Dendra2::tau transgenic C. elegans, we identified hpo-10/LENG8 as a novel genetic enhancer of tau accumulation. Recently discovered functions of hpo-10/LENG8 in the mRNA export and quality control pathway suggests that this gene plays a translationally relevant role in neuronal health and tauopathy pathogenesis.