The unfolded protein response and Alzheimer's disease.
Disruption of calcium homeostasis, inhibition of protein glycosylation, and reduction of disulfide bonds provoke accumulation of unfolded protein in the endoplasmic reticulum (ER), and are therefore a type of 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, GRP94 and protein disulfide isomerase to facilitate protein folding. This induction system is termed the unfolded protein response. Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6.
Imaizumi
K
K
Division of Structural Cell Biology, Nara Institute of Science and Technology, Takayama, Ikoma Nara, Japan. imaizumi@bs.aist-nara.ac.jp
Miyoshi
K
K
Katayama
T
T
Yoneda
T
T
Taniguchi
M
M
Kudo
T
T
Tohyama
M
M
D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006031:Glycosylation; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000235:genetics; D017510:Protein Folding; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction; D014158:Transcription, Genetic
D002868:Chromosomal Proteins, Non-Histone; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; D002118:Calcium