Promotion of hyperphosphorylation by frontotemporal dementia tau mutations.
Mutations in the tau gene are known to cosegregate with the disease in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, the molecular mechanism by which these mutations might lead to the disease is not understood. Here, we show that four of the FTDP-17 tau mutations, R406W, V337M, G272V, and P301L, result in tau proteins that are more favorable substrates for phosphorylation by brain protein kinases than the wild-type, largest four-repeat protein tau4L and tau4L more than tau3L. In general, at all the sites studied, mutant tau proteins were phosphorylated faster and to a higher extent than tau4L and tau4L > tau3L. The most dramatic difference found was in the rate and level of phosphorylation of tau4L(R406W) at positions Ser-396, Ser-400, Thr-403, and Ser-404. Phosphorylation of this mutant tau was 12 times faster and 400% greater at Ser-396 and less than 30% at Ser-400, Thr-403, and Ser-404 than phosphorylation of tau4L. The mutated tau proteins polymerized into filaments when 4-6 mol of phosphate per mol of tau were incorporated, whereas wild-type tau required approximately 10 mol of phosphate per mol of protein to self-assemble. Mutated and wild-type tau proteins were able to sequester normal tau upon incorporation of approximately 4 mol of phosphate per mol of protein, which was achieved at as early as 30 min of phosphorylation in the case of mutant tau proteins. These findings taken together suggest that the mutations in tau might cause neurodegeneration by making the protein a more favorable substrate for hyperphosphorylation.
Alonso
Alejandra del C
Adel C
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY 10314-6399, USA.
Mederlyova
Anna
A
Novak
Michal
M
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D001921:Brain / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17; D004247:DNA / Q000378:metabolism; D003704:Dementia / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015151:Immunoblotting; D016296:Mutagenesis; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation; D020033:Protein Isoforms; D011494:Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics*
D020033:Protein Isoforms; D011994:Recombinant Proteins; D016875:tau Proteins; D013912:Threonine; D012694:Serine; D004247:DNA; D011494:Protein Kinases