A report in the current Nature Cell Biology describes a mechanism by which presenilin-1 (PS-1) mutations can interfere with protein folding. Kazunori Imaizumi of Osaka University and colleagues suggest that this process underlies neurodegeneration in this form of familial Alzheimer's. In particular, the PS-1 mutations were found to interfere with a cell's unfolded protein response (UPR), a set of mechanisms designed to reduce the "stress" caused by the presence of unfolded proteins in the endoplasmic reticulum (ER). Among the mediators of the UPR are the molecule IRE1, which senses the stress on the ER, and various "chaperone" proteins that are induced by IRE1 and that facilitate protein folding.
In a series of in vitro experiments, Imaizumi and his colleagues found that under ER stress, cells expressing mutant PS-1 did not respond with the necessary increases of the chaperone protein GRP78 and were more likely to die. They traced this failure of GRP78 induction to interference by mutant PS-1 with autophosphorylation of the sensor molecule, IRE1. The researchers were also able to restore the UPR in mutant-PS-1-expressing cells and keep those cells alive by adding exogenous GRP78.
Finally, they looked for evidence of this process in humans. They found that levels of chaperone proteins were downregulated in specimens from the brains of Alzheimer's patients. The downregulation was greater in familial than in sporadic Alzheimer's specimens. IRE1 phosphorylation and GRP78 expression, say the authors, should thus be considered promising targets for therapies for both familial and sporadic Alzheimer's.—Hakon Heimer