The Influence of Genetic Diversity on Tauopathy

Abstract

The presence of misfolded tau proteins is a hallmark of a group of neurodegenerative diseases termed tauopathies. This heterogeneous group of disorders includes Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, and dozens of related dementias. One common approach to research these diseases is to use clonally inbred animal strains to investigate druggable pathways that can be translated to human patients. Although clonally inbred lines offer a standard to limit inter-laboratory variability, selecting a single genetic background does not allow researchers to consider the natural population-level genetic diversity seen in humans. Recent studies have demonstrated that introducing genetic diversity into animal models of complex diseases improves translatability to patient populations. Within the context of neurodegeneration, several studies have found that brain pathology in mouse models of amyloid-β accumulation is modified by genetic variance within a subset of wild-derived mouse strains. Several findings have demonstrated that non-C57BL/6J mouse strains alter tau pathology, however, the effect of these wild-derived strains on tau is unknown. To understand how genetically diverse animal models respond to the presence of pathological tau, we generated cohorts of wild-derived mice and fruit flies that express humanized mutant tau. We found that the formation of proteopathic prion-like tau seeds was dependent on the genetic backgrounds of these wild-derived animal models. Interestingly, we showed that multi-omic analysis of PWK/PhJ reveals immune dysregulation not seen in classically inbred models of tau pathology. Furthermore, genetic mapping in a novel panel of wild-derived fruit flies revealed novel genetic modifiers of tau seeds. We demonstrate how tauopathy is influenced by genetic diversity and how these models may be used as a resource to study tau-driven neurodegenerative diseases. Taken together, the data suggest that introducing genetic diversity into animal models of mutant tau expression may increase translation to patients suffering from tauopathy.