Distinct FTDP-17 missense mutations in tau produce tau aggregates and other pathological phenotypes in transfected CHO cells

Multiple tau gene mutations are pathogenic for hereditary frontotemporal de mentia and parkinsonism linked to chromosome 17 (FTDP-17), with filamentous tau aggregates as the major lesions in the CNS of these patients. Recent s tudies have shown that bacterially expressed recombinant tau proteins with FTDP-17 missense mutations cause functional impairments, i.e., a reduced ab ility of mutant tau to bind to or promote the assembly of microtubules. To investigate the biological consequences of FTDP-17 tau mutants and assess t heir ability to form filamentous aggregates, we engineered Chinese hamster ovary cell lines to stably express tau harboring one or several different F TDP-17 mutations and showed that different tau mutants produced distinct pa thological phenotypes. For example, DeltaK, but not several other single ta u mutants (e.g., V337 M, P301L, R406W), developed insoluble amorphous and f ibrillar aggregates, whereas a triple tau mutant (VPR) containing V337M, P3 01L, and R406W substitutions also formed similar aggregates. Furthermore, t he aggregates increased in size over time in culture. Significantly, the fo rmation of aggregated DeltaK and VPR tau protein correlated with reduced af finity of these mutants to bind microtubules. Reduced phosphorylation and a ltered proteolysis was also observed in R406W and DeltaK tau mutants. Thus, distinct pathological phenotypes, including the formation of insoluble fil amentous tau aggregates, result from the expression of different FTDP-17 ta u mutants in transfected Chinese hamster ovary cells and implies that these missense mutations cause diverse neurodegenerative FTDP-17 syndromes by mu ltiple mechanisms.