The natural osmolyte trimethylamine N-oxide (TMAO) restores the ability of mutant 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 chromosome 17 (FTDP-17). Most coding region mutations effect a reduced ability of tau protein to interact with microtubules and lead to the formation of a filamentous pathology made of hyperphosphorylated tau. Here we show that trimethylamine N-oxide (TMAO) restores the ability of tau with FTDP-17 mutations to promote microtubule assembly. To mimic phosphorylation, serine and threonine 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 residues), TMAO increased the ability of mutant tau to promote microtubule assembly. However, it had no significant effect on heparin-induced assembly of tau into filaments.
Smith
M J
MJ
Medical Research Council Laboratory of Molecular Biology, Hills Road, CB2 2QH, Cambridge, UK.
Crowther
R A
RA
Goedert
M
M
D019943:Amino Acid Substitution; D002886:Chromosomes, Human, Pair 17; D003001:Cloning, Molecular; D004926:Escherichia coli; D006801:Humans; D007700:Kinetics; D008744:Methylamines / Q000494:pharmacology*; D008870:Microtubules / Q000648:ultrastructure*; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D008744:Methylamines; D011994:Recombinant Proteins; D016875:tau Proteins; C005855:trimethyloxamine