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Results: 2

Figure 2

Figure 2. Caspase cleavage in Alzheimer’s disease. From: Cell death in the nervous system.

An antibody specific for the neoepitope generated by cleavage of APP at the caspase-cleavage site, Asp 664, demonstrates reactivity (brown) in the hippocampus of a patient with Alzheimer’s disease.

Dale E. Bredesen, et al. Nature. 2006 October 19;443(7113):796-802.
Figure 1

Figure 1. Misfolded proteins and endoplasmic-reticulum stress. From: Cell death in the nervous system.

a, In addition to its role as an ER chaperone protein, BiP also regulates the activation of the three proximal ER-stress transducers — IRE1, PERK and ATF6. All three transducers contain an amino-terminal luminal domain that interacts with BiP. Under normal conditions, BiP serves as a negative regulator of IRE1, PERK and ATF6 activation. When misfolded proteins accumulate and result in ER stress, BiP binds to these proteins. BiP is thus released from the transducers, which are consequently activated. The activation of all three proximal sensors results in reduction in the amount of new protein translocated into the ER lumen, increased degradation of ER-localized proteins and increased proteinfolding capacity of the ER. b, BiP release from PERK correlates with oligomerization, trans-autophosphorylation and activation of downstream signalling by PERK. PERK-dependent phosphorylation of eIF2α on Ser 51 leads to attenuation of protein translation and thereby reduces the workload of the ER. c, BiP release from ATF6 permits transport of AFT6 to the Golgi compartment for regulated intramembrane proteolysis by site-1 protease (S1P) and site-2 protease (S2P) to generate a 50-kDa cytosolic b-ZIP-containing fragment (ATF6DC). ATF6DC translocates to the nucleus to activate ER-stress inducible target genes that code for proteins involved in protein folding. This BiP-regulated activation provides a direct mechanism to sense the folding capacity of the ER. d, Accumulation of misfolded proteins in the ER causes BiP to release IRE1. IRE1 is a type I transmembrane protein that contains both a serine/threonine kinase domain and an endoribonuclease domain; the latter processes an intron from X-box protein 1 (XBP1) mRNA, rendering it competent for translation to produce the 41-kDa XBP1(S) protein. Unspliced XBP1 mRNA encodes a basic leucine-zipper protein, XBP1(U), that lacks transactivation activity and is more labile than XBP1(S). XBP1(S) binds to the promoters of several genes involved in retrograde transport of misfolded proteins from the ER to the cytosol and in ER-induced protein degradation.

Dale E. Bredesen, et al. Nature. 2006 October 19;443(7113):796-802.

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