title: Lithium treatment induces proteasomal degradation of over-expressed acetylcholinesterase (AChE-S) and inhibit GSK3β.
abstract: Lithium is one of the most widely used mood-stabilizing agents for the treatment of bipolar disorder. Lithium is also a potent inhibitor of glycogen synthase kinase-3β (GSK3β) activity, which is linked to Alzheimer's disease (AD). In experiments with cultured HEK293T cells, we show here that GSK3β stabilizes synaptic acetylcholinesterase (AChE-S), a critical component of AD development. Cells treated with lithium exhibited rapid proteasomal degradation of AChE-S. Furthermore treatment of the cells with MG132, an inhibitor of the 26S proteasome, prevented the destabilizing effect of lithium on AChE-S. Taken together, these findings suggest that regulation of AChE-S protein stability may be an important biological target of lithium therapy.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Jing
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Ouyang
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Zhang
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics* / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D019943:Amino Acid Substitution; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004795:Enzyme Stability / Q000187:drug effects; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D007976:Leupeptins; D011994:Recombinant Proteins; D008094:Lithium; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C548246:Ache protein, rat; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde