Distinctively high seeding competency of tau species in globular glial tauopathy
Daheun Chung1,2, Yari Carlomagno, Ph.D2, Laura J. Lewis-Tuffin, Ph.D.3, Irene K. Yan3, Michael DeTure, Ph.D.2, Tushar C. Patel, M.D., Ch.B.3, Dennis W. Dickson, M.D.1,2, Casey N. Cook, Ph.D1, Leonard Petrucelli, Ph.D.1,2*
1Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences; 2Department of Neuroscience; 3Department of Cancer Biology, Mayo Clinic, Jacksonville, FL
The abnormal aggregation of hyperphosphorylated microtubule-associated protein tau is a pathological hallmark shared by various neurodegenerative diseases collectively called tauopathies. While exact mechanisms underlying seeding and cell-to-cell transmission of pathological tau species still remain elusive, growing evidence has shown that distinct tau strains are implicated in various tauopathies. Globular glial tauopathy (GGT) is a rare 4R tauopathy that is characterized by large, globular tau inclusions within glial cells. Given that the pathologic tau deposition observed in GGT is quite unique relative to other tauopathies, we wanted to determine whether differences in seeding competency between GGT and other tauopathies could be detected in postmortem brain tissue using the mutant tau biosensor cell line. This analysis revealed that brain lysates from both mutant and sporadic GGT cases exhibited significantly higher seeding competency (as revealed by FRET intensity in the biosensor cell line) than other tauopathies, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD), as well as controls. Consistent with previous reports, the extracellular vesicle fraction (EV) also contained significant seeding activity, which was much higher in GGT cases compared to other tauopathies in our seeding assay. We also found that GGT brain and EV samples induced numerous tau inclusions with a very distinct, globular morphology in the biosensor cell line, which was markedly different from those induced by CBD, PSP, and AD samples. Importantly, this robust tau seeding induced by GGT samples was independent of tau levels. These data indicate that tau species in GGT cases exhibit a unique morphology with high seeding competency compared to those from other tauopathies, which might be reflective of inherent differences in the tendency of glial versus neuronal tau pathology to propagate.