Early onset rapidly progressive frontotemporal dementia due to a novel MAPT P301A variant with functional validation of pathogenicity

Abstract Frontotemporal dementia represents a group of clinical syndromes characterized by progressive changes in behavior or language that are associated with frontotemporal lobe atrophy. Around 40% of FTD cases are familial, with mutations in MAPT representing a major familial form. Among MAPT variants, substitutions at codon 301 – notably P301L, P301S, and P301T – are established pathogenic causes of autosomal-dominant frontotemporal lobar degeneration (FTLD). In contrast, a P301A substitution has not, to our knowledge, been reported in patients. Here, we describe a novel P301A MAPT variant presenting with early onset, rapidly progressive FTLD. We show, using biochemical and cellular assays, that P301A tau fibrillizes faster and seeds more robustly than wild-type and P301L tau, with performance comparable to P301S. These findings suggest the P301A variant is pathogenic. This work expands the MAPT variant spectrum in FTLD, and supports a model in which distinct substitutions at P301 differentially influence tau aggregation and prion-like propagation.