Microtubule-associated protein tau is a substrate of ATP/Mg(2+)-dependent proteasome protease system.
Deposition of hyperphosphorylated microtubule-associated protein tau is a recognized pathological process in Alzheimer's disease (AD) brain, however, the mechanism leading to tau accumulation is still not understood. In the present study, we found that different forms of tau, including phosphorylated tau (PHF-1) and non-phosphorylated tau (Tau-1) as well as total tau (Tau-5) in rat brain cortex extract, were degraded when it was co-incubated with ATP and MgCl(2) at 33 degrees C in vitro, and non-phosphorylated tau at Tau-1 epitope was more accessible to the ATP/Mg(2+)-depended proteolysis. With the increase of ATP and MgCl(2) concentration from 5 mM to 20 mM, increased degradation of tau was observed. ATP/Mg(2+)-induced degradation of tau was blocked by lactacystin, a specific proteasome inhibitor and was enhanced by sodium dodecyl sulphate (SDS), a commonly used in vitro proteasome activator, and polyubiquitinated tau with high molecular weight was detected in the presence of lactacystin. Hyperphosphorylated tau isolated from AD brain (AD p-tau) was also partially degraded when it was incubated with rat brain cortex extract in the present of ATP/Mg(2+), and the degradation of AD p-tau was also enhanced by SDS and was inhibited by lactacystin. This study has demonstrated that tau, both phosphorylated and non-phosphorylated, is a substrate of ATP/Mg(2+)-depended proteasome. To our knowledge, this is the first report providing direct evidence that tau is degraded by 26S proteasome in an ubiquitin- and ATP-dependent manner.
Zhang
J Y
JY
Pathophysiology Department, Neuroscience Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Liu
S J
SJ
Li
H L
HL
Wang
J-Z
JZ
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008274:Magnesium / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D025801:Ubiquitin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D025801:Ubiquitin; D016875:tau Proteins; D000255:Adenosine Triphosphate; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D008274:Magnesium