Project Summary/Abstract:
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.