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 t he endoplasmic reticulum (ER), and are therefore a type of 'ER stress'. Nor mal cells respond to ER stress by increasing transcription of genes encodin g ER-resident chaperones such as GRP78/BiP, GRP94 and protein disulfide iso merase to facilitate protein folding. This induction system is termed the u nfolded protein response. Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vul nerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress tra nsducers such as IRE1, PERK and ATF6. (C) 2001 Elsevier Science B.V. All ri ghts reserved.