Pathological Implications of the tau-RNA Interaction

The protein tau (MAPT, tau) aberrantly accumulates in a family of neurodegenerative diseases (collectively termed tauopathies); the most prevalent and notable of these diseases being Alzheimer’s Disease (AD). The modification of tau, through post-translational modifications or mutation, has been associated with the toxic accumulation that occurs in neurodegenerative disorders. However, our group as well as others have investigated if the interaction between tau and normal cellular RNA can play a role in the accumulation and eventual toxicity of tau. We identified RNA motifs enriched as tau-binders in distinct phases of disease progression: from persons presenting no tauopathy markers or clinical manifestations of neurodegeneration, to those without cognitive impairment but some pathological tau detected post mortem, to those diagnosed with AD later confirmed at autopsy. These motifs and the dispersal of these motifs throughout disease stage suggest that some RNA-tau interactions may be protective against or neutral to condensate or pathology development, whereas other motifs may enhance condensates and pathology. If the studies proposed herein that follow these data are successful, we may be able to answer questions about specificity of mRNA motifs for forming condensates with tau, the fate of these mRNA interacting with tau, and (eventually) the impact of these interactions and condensates on pathology. Importantly, if we are able to identify RNA motifs that either enhance or inhibit the formation of biomolecular condensates, this information could then be modified into therapeutic strategies.