Alzheimer’s Disease and Alzheimer’s Disease Related Disorders belong to a devastating class of neurodegenerative diseases called tauopathies, marked by pathologic aggregation of hyper-phosphorylated tau protein (phospho-tau)1. An early event in the onset of tauopathies is the formation of pathologic-stress granules (p-SGs); cytotoxic biomolecular condensates (BMCs) consisting of toxic phospho-tau oligomers and RNA-binding proteins (RBPs) T-Cell Intracellular Antigen 1 (TIA1) and Splicing Factor Proline and Glutamine Rich (SFPQ) that accumulate in the cytoplasm of neural cells2–4,8. While it is evident that p-SGs play an important role in the pathogenesis of tauopathy2,3,5,75, it is unknown how they form and how they impact homeostatic functions of the proteins they sequester. Defects in axonal transport have been established as an early event accompanying phospho-tau pathology, with conformational changes in pathologic tau leading to inhibition of anterograde axonal transport through kinesin motors32–34. Since several SG associated RBPs, including SFPQ, rely on kinesins to transport mRNAs9,10, we propose that early deficits in axonal transport lead to buildup of transport RBPs in the cytoplasm, where they aggregate, contributing to formation of p-SGs. Once sequestered in p-SGs, we predict that RBP homeostatic functions are disrupted, enhancing tau-mediated neurodegeneration. To test our model, we will use innovative methods for interrupting axonal transport in WT and P301S MAPT mutant human induced cortical neurons (iCNs) and motor neurons (iMNs). We will evaluate whether disruption of particular transport programs accelerates formation of the BMCs that are the p-SGs. To determine whether sequestration of RBP SFPQ in p-SGs disrupts critical homeostatic functions in the nucleus and/or the axons of cortical and motor neurons, we will again use WT and P301S MAPT mutant human induced cortical neurons (iCNs) and motor neurons (iMNs) and interrogate the multiple essential functions of SFPQ57, including DNA repair, nuclear mRNA export, and axonal mRNA transport. Results from these studies will identify early targets for pharmacologic intervention in the pathogenesis of tauopathy and identify essential differences in the onset of disease in different cells types of the central nervous system. 

Funded by NIA