A Molecular Investigation into the Mechanisms of Tau and TDP-43 Mediated Neurodegeneration

Abstract

The pathological aggregation of the microtubule-binding protein tau and RNA-binding protein TDP-43 constitute two major hallmarks of neurodegenerative disease shared across numerous human disorders. The molecular mechanisms mediating neuron death by tau and TDP-43 toxicity in disease are not well understood. Across transgenic C. elegans and mouse models of disease, and in patient tissue, we have applied genetic, biochemical, and transcriptomic techniques to provide insight into the pathobiology of human neurodegenerative disease. Through several scientific projects, we nominate a role for RNA nuclear speckle components in the progression of tauopathy and a role for TDP-43 gain-of-function disruptions to RNA metabolism in TDP-43 proteinopathy. Our results join a corpus of evidence dissecting basic biology to provide the foundation for future clinical interventions for age-related neurodegenerative disease.