Functional differences of tau isoforms containing 3 or 4 C-terminal repeat regions and the influence of oxidative stress.
We report functional differences between tau isoforms with 3 or 4 C-terminal repeats and a difference in susceptibility to oxidative conditions, with respect to the regulation of microtubule dynamics in vitro and tau-microtubule binding in cultured cells. In the presence of dithiothreitol in vitro, a 3-repeat tau isoform promotes microtubule nucleation, reduces the tubulin critical concentration for microtubule assembly, and suppresses dynamic instability. Under non-reducing conditions, threshold concentrations of 3-repeat tau and tubulin exist below which this isoform still promotes microtubule nucleation and assembly but fails to reduce the tubulin critical concentration or suppress dynamic instability; above these threshold concentrations, amorphous aggregates of 3-repeat tau and tubulin can be produced at the expense of microtubule formation. A 4-repeat tau isoform is less sensitive to the oxidative potential of the environment, behaving under oxidative conditions similarly to the 3-repeat isoform under reducing conditions. Under conditions of oxidative stress, in Chinese hamster ovary cells stably expressing either 3- or 4-repeat tau, 3-repeat tau disassociates from microtubules more readily than the 4-repeat isoform, and tau-containing high molecular weight aggregates are preferentially observed in lysates from the Chinese hamster ovary cells expressing 3-repeat tau, indicating greater susceptibility of 3-repeat tau to oxidative conditions, compared with 4-repeat tau in vivo.
Utton
M A
MA
Department of Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom. m.utton@iop.kcl.ac.uk
Gibb
G M
GM
Burdett
I D
ID
Anderton
B H
BH
Vandecandelaere
A
A
D000818:Animals; D016466:CHO Cells; D002455:Cell Division; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D019163:Reducing Agents / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014162:Transfection; D016875:tau Proteins / Q000737:chemistry* / Q000502:physiology*
D020033:Protein Isoforms; D011994:Recombinant Proteins; D019163:Reducing Agents; D016875:tau Proteins