Missense tau mutations identified in FTDP-17 have a small effect on tau-microtubule interactions

Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is a group of related disorders frequently characterized by the formation of tau inclusions in neurons and glial cells. To determine whether the form ation of tau inclusions in FTDP-17 results from an alteration in the abilit y of mutant tau to maintain the microtubule (MT) system, we compared wild t ype four-repeat tau with three FTDP-17 mutants (P301L, V337M and R406W) for their ability to bind MT, promote MT assembly and bundling. According to i n vitro binding and assembly assays, P301L is the only mutant that demonstr ates a small, yet significant reduction, in its affinity for MT while both P301L and R406W have a small reduction in their ability to promote tubulin assembly. Based on studies of neuroblastoma and CHO cells transfected with GFP-tagged tau DNA constructs, both mutant and wild type tau transfectants were indistinguishable in the distribution pattern of tau in terms of co-lo calization with MT and generation of MT bundles. These results suggest that missense mutation of tau gene do not have an immediate impact on the integ rity of MT system, and that exposure of affected neurons to additional insu lts or factors (e.g., aging) may be needed to initiate the formation of tau inclusions in FTDP-17. (C) 2000 Published by Elsevier Science B.V. All rig hts reserved.