Mutation in the tau gene in familial multiple system tauopathy with presenile dementia

TLDR

Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease characterized by abundant filamentous tau protein pathology and belongs to the chromosome‑17 linked frontotemporal dementias (FTDP‑17), a major class of inherited dementias with an unknown genetic basis. The identified G→A transition occurs at the 3′ nucleotide adjacent to the GT splice‑donor site, disrupting a predicted stem‑loop structure. The intronic mutation in the tau gene shifts the balance toward four‑repeat tau isoforms, producing filaments composed solely of these isoforms, thereby demonstrating that tau dysregulation drives neurodegeneration and establishing the tau gene as the FTDP‑17 locus with implications for Alzheimer’s disease and other tauopathies.

Abstract

Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology. It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown. We now report a G to A transition in the intron following exon 10 of the gene for microtubule-associated protein tau in familial MSTD. The mutation is located at the 3' neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer's disease and other tauopathies.