Elucidating the Mechanisms that Underlie Tau Aggregation and Neurotoxicity

PROJECT SUMMARY/ABSTRACT This proposal entails a five-year mentored career development plan that studies mechanisms of tau aggregation in Alzheimer's disease and frontotemporal lobar degeneration. This proposal includes technical training in iPSC-derived neuron cultures, CRISPR functional genomics and bioinformatics approaches, and in- depth neuropathologic analysis. The training plan also incorporates skills required to maintain an independent research group, including scientific communication, grant writing, mentorship skills, and lab management strategies. To achieve these goals, the candidate, Dr. Sarah Kaufman, has assembled a multidisciplinary mentorship team that includes Dr. Martin Kampmann (mentor), Dr. Bill Seeley (co-mentor), and advisory members Dr. Bruce Miller and Dr. Jason Gestwicki. Together, this proposal will allow her to establish a rigorous independent laboratory that combines her previous graduate training, clinical interest in Alzheimer's disease and frontotemporal dementia, and scientific expertise in tauopathies to become a leader in neurodegenerative disease research. Tauopathies including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau) are devastating neurodegenerative diseases that currently affect over 30 million people worldwide. Tau aggregates in AD and FTLD-tau adopt unique, disease-specific conformations, or “strains,” that deposit in selectively vulnerable neurons. Different tau strains are now believed to underlie the different disease phenotypes and atrophy patterns observed across tauopathies. However, the mechanisms that give rise to different tau strains and their link to selective vulnerability and neuronal loss are not known. Several human induced pluripotent stem cell (iPSC) derived excitatory neuron (iNeuron) models have been developed to study tauopathies. However, these models do not readily accumulate tau aggregates, which has hindered their use when studying mechanisms of tau strains or selective vulnerability. This proposal describes the creation of a novel iNeuron model that stably maintains full-length tau aggregates seeded from human tauopathies that are associated with distinct tau strains. An initial large-scale CRISPRi screen identified several novel regulators of tau aggregation in this iNeuron model, including the lesser-known ubiquitin-like UFMylation pathway that plays an important role in protein homeostasis, and several RNA binding proteins known to directly interact with tau protein. Aim 1 of this proposal will elucidate the role of RNA binding proteins in tau aggregation and selective vulnerability across different tau strains, followed by analysis in human tauopathy subjects. Aim 2 will elucidate the mechanisms by which UFMylation modulates tau aggregation in neurons. Together, the proposed research will provide important insight into the mechanisms that underlie tau aggregation and the link between tau strains and different patterns of selective vulnerability observed across tauopathies.