title: FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions.
abstract: FTDP-17 mutations in the tau gene lead to early onset frontotemporal dementias characterized by the pathological aggregation of the microtubule-associated protein tau. Tau aggregation is closely correlated with the progression and severity of localized atrophy of certain regions in the brain. These mutations are primarily located in or near the microtubule-binding repeat regions of tau and can have vastly different effects on the protein. Some mutations have been linked to effects such as increased levels of aggregation, hyperphosphorylation, defects in mRNA splicing, and weakened interaction with microtubules. Given the differential effects of the mutations, it may not be surprising that the pathology associated with FTDP-17 can vary widely as well. Despite this variety, several of the mutations are commonly used interchangeably as aggregation inducers for in vitro and in vivo models of tauopathies. We generated recombinant forms of 12 FTDP-17 mutations chosen for their predicted effects on the charge, hydrophobicity, and secondary structure of the protein. We then examined the effects that the mutations had on the properties of in vitro aggregation of the protein and its ability to stabilize microtubule assembly. The group of mutations induced very different effects on the total amount of aggregation, the kinetics of aggregation, and filament morphology. Several of the mutations inhibited the microtubule stabilization ability of tau, while others had very little effect compared to wild-type tau. These results indicate that the mechanisms of disease progression may differ among FTDP-17 mutations and that the effects of the varying mutations may not be equal in all model systems.
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Combs
authors.forename: T Chris
authors.initials: TC
authors.lastname: Gamblin
mesh_terms: D006801:Humans; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure*; D009154:Mutation; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism / Q000648:ultrastructure; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D014404:Tubulin; D016875:tau Proteins