Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain.
According to the amyloid hypothesis for the pathogenesis of Alzheimer disease, beta-amyloid peptide (betaA) directly affects neurons, leading to neurodegeneration and tau phosphorylation. In rat hippocampal culture, betaA exposure activates tau protein kinase I/glycogen synthase kinase 3beta (TPKI/GSK-3beta), which phosphorylates tau protein into Alzheimer disease-like forms, resulting in neuronal death. To elucidate the mechanism of betaA-induced neuronal death, we searched for substrates of TPKI/GSK-3beta in a two-hybrid system and identified pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA in mitochondria. PDH was phosphorylated and inactivated by TPKI/GSK-3beta in vitro and also in betaA-treated hippocampal cultures, resulting in mitochondrial dysfunction, which would contribute to neuronal death. In cholinergic neurons, betaA impaired acetylcholine synthesis without affecting choline acetyltransferase activity, which suggests that PDH is inactivated by betaA-induced TPKI/GSK-3beta. Thus, TPKI/GSK-3beta regulates PDH and participates in energy metabolism and acetylcholine synthesis. These results suggest that TPKI/GSK-3beta plays a key role in the pathogenesis of Alzheimer disease.
Hoshi
M
M
Mitsubishi Kasei Institute of Life Sciences, Tokyo, Japan.
Takashima
A
A
Noguchi
K
K
Murayama
M
M
Sato
M
M
Kondo
S
S
Saitoh
Y
Y
Ishiguro
K
K
Hoshino
T
T
Imahori
K
K
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005333:Fetus; D038362:Glycogen Synthase Kinase 3; D006624:Hippocampus / Q000201:enzymology*; D006706:Homeostasis; D015151:Immunoblotting; D007150:Immunohistochemistry; D007700:Kinetics; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology*; D010766:Phosphorylation; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D013347:Subcellular Fractions / Q000201:enzymology / Q000648:ultrastructure
D011768:Pyruvate Dehydrogenase Complex; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase