Alterations of chaperone protein expression in presenilin mutant neurons in response to glutamate excitotoxicity.
Mutations in the presenilin-1 (PS1) gene underlie the most common form of familial dementia of the Alzheimer type (DAT). We demonstrated previously that the expression of PS1 with a M146V mutation in transgenic mice potentiates glutamate toxicity to neurons, due to an altered calcium homeostasis. Here, using a subtractive cDNA library approach, we report the identification of several genes, the altered expression of which may be associated with this unique PS1-related vulnerability to glutamate. The identified genes, including chaperonin subunit 2 and nucleophosmin 1/B23, are involved in the intracellular trafficking of proteins and ions. Northern blot analysis revealed that the effect of glutamate on calcium-binding proteins was augmented in neurons from PS1 mutation mice, compared with neurons from mice lacking other genes relevant to the pathogenesis of DAT (FE65 and APOE) or neurons from control wild-type mice. Interestingly, mRNA for two chaperone proteins were expressed at lower levels specifically in neurons from PS1 mutant mice. These findings suggest that PS1 mutations may, in part, contribute to the development of DAT via altered expression of chaperone proteins.
Maezawa
Izumi
I
Department of Pathology, University of Washington, Seattle 98195-7470, USA.
Wang
Baiping
B
Hu
Qubai
Q
Martin
George M
GM
Jin
Lee-Way
LW
Oshima
Junko
J
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D018833:Chaperonins / Q000096:biosynthesis / Q000187:drug effects*; D020869:Gene Expression Profiling; D015723:Gene Library; D018698:Glutamic Acid / Q000633:toxicity*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D053764:Presenilin-1
C486243:Apbb1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D053764:Presenilin-1; D000090243:Nucleophosmin; D018698:Glutamic Acid; D018833:Chaperonins