Aberrant proteomes in tauopathy: revealing functional consequences via multimodal proteomics

SUMMARY Tauopathies including Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are a group of devastating neurodegenerative diseases that currently affect over 30 million people worldwide. Tau pathology correlates with neuronal loss in AD and several mutations that increase tau aggregation cause familial forms of FTD, suggesting tau aggregation plays an important role in the pathogenesis of neurodegeneration in these diseases. Indeed, tau-lowering therapies are being evaluated in clinical trials for AD. Despite this central importance of tau in the pathogenesis of AD and related tauopathies, the molecular and cellular mechanisms by which pathological tau drives neurodegeneration are poorly understood. Thus, a systematic elucidation of these mechanisms would transform our understanding of AD and related dementias, and also open up new avenues for therapeutic approaches that could be beneficial in patients in which tau pathology has already been established and downstream effects have already affected neuronal function. Here, we propose to combine our expertise in mass spectrometry-based proteomics (Swaney) and functional genomics (Kampmann) to comprehensively map the impact of tau pathology on the proteome, which we expect to be mediated in part through disruptions in mRNA splicing, and measure the functional consequences of this pathology with cell type, subcellular, and molecular resolution. This work leverages AD mouse models and human iPSC tauopathy models for discovery of protein drivers of tauopathy, as well as validates such drivers in human post-mortem brains. Importantly, our approach will measure multiple modalities of protein function to provide a holistic view of the diversity of functional consequences incurred in neurons and brains with tau pathology. We anticipate these results will deepen our understanding of molecular mechanisms of AD and ADRD and have the potential to pinpoint novel therapeutic targets.