Distinct tau filament folds in familial frontotemporal dementia due to the MAPT S305I mutation

Abstract Frontotemporal lobar degeneration with tau inclusions (FTLD-tau) comprise a class of fatal heterogeneous neurodegenerative diseases. Approximately 10% arise from pathogenic MAPT mutations and often cause severe, early-onset disease with pathology that is distinct yet partially overlapping with sporadic cases. Here, we evaluated post-mortem tissue from a patient with FTLD-tau due to MAPT S305I showing neuropathology most consistent with argyrophilic grain disease (AGD), a prevalent limbic tauopathy of aging. Structures determined by cryo-electron microscopy reveal tau filament folds that differ from those found in sporadic AGD or other tauopathies and feature a 4-layer architecture stabilized by the Ile substitution within its core. Comparative structural analysis reveals conserved motifs are shared among AGD, corticobasal degeneration, and MAPT P301T. A well-defined density stacks along a cationic cleft, indicative of a bound RNA-like polyanion or small-molecule. In vitro analysis shows the S305I mutation promotes fibrilization relative to normal tau. These results demonstrate that MAPT S305I stabilizes a distinct aggregation-prone tau fold that likely contributes to disease pathology and heterogeneity beyond its known splicing defects, and underscore potential limitations of using the most pathologically similar genetic form as a model for sporadic FTLD-tau. Competing Interest Statement W.F.D. is a member of the scientific advisory boards of Alzheon Inc., Pliant, Longevity, CyteGen, Amai, and ADRx Inc., none of which contributed support for this study. W.W.S has received consulting fees from BridgeBio, Guidepoint Global, Inc., and GLG Council; speaker honoraria from Verge Genomics; and compensation as a member of the scientific advisory board for Lyterian Therapeutics, none of which contributed support for this study. The remaining authors declare no competing interests. Footnotes The distribution/reuse options have been modified.