The natural osmolyte trimethylamine N-oxide (TMAO) restores the ability ofmutant tau to promote microtubule assembly

Coding region and intronic mutations in the gene for microtubule-associated protein tau cause frontotemporal dementia and Parkinsonism linked to chrom osome 17 (FTDP-17), Most coding region mutations effect a reduced ability o f tau protein to interact with microtubules and lead to the formation of a filamentous pathology made of hyperphosphorylated tau. Here we show that tr imethylamine N-oxide (TMAO) restores the ability of tau with FTDP-17 mutati ons to promote microtubule assembly. To mimic phosphorylation, serine and t hreonine residues in tau were singly or multiply mutated to glutamic acid, resulting in a reduced ability of tau to promote microtubule assembly. With the exception of the most heavily substituted protein (27 glutamic acid re sidues), TMAO increased the ability of mutant tau to promote microtubule as sembly. However, it had no significant effect on heparin-induced assembly o f tau into filaments, (C) 2000 Federation of European Biochemical Societies . Published by Elsevier Science B.V, All rights reserved.