Tau aggregation and seeding analyses of two novel MAPT variants found in patients with motor neuron disease and progressive parkinsonism.

Variants in the microtubule-associated protein tau (MAPT) gene cause the genetic tauopathies, a subgroup of frontotemporal dementia (FTD) disorders. Through genetic screening of 165 cases possibly associated with tauopathies, including 88 Alzheimer's disease, 26 behavioral variant FTD, eight primary progressive aphasia, nine FTD with motor neuron disease, 21 progressive supranuclear palsy, and 13 corticobasal syndrome, we identified two novel MAPT variants: a heterozygous missense variant, p.P160S, in a patient with FTD with motor neuron disease and a heterozygous insertional variant, p.K298_H299insQ, in three patients with familial progressive supranuclear palsy. The corresponding recombinant tau proteins showed reduced microtubule assembly and increased aggregation by thioflavin S assay. Exon trapping analysis showed that p.K298_H299insQ resulted in the overproduction of 4-repeat tau. In a cell-based model, p.K298_H299insQ had both a higher aggregation ability and seeding activity compared with wild-type tau. These findings indicate that both p.P160S and p.K298_H299insQ may relate to neurodegeneration.