Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response

Topic: Brain proteins, microglia and lab models

Missense mutations in the human presenilin-1 (PS1) gene, which is found on chromosome 14, cause early-onset familial Alzheimer's disease (FAD). FAD-linked PS1 variants alter proteolytic processing of the amyloid precursor protein and cause an increase in vulnerability to apoptosis induced by various cell stresses. However, the mechanisms responsible for these phenomena are not clear. Here we report that mutations in PS1 affect the unfolded-protein response (UPR), which responds to the increased amount of unfolded proteins that accumulate in the endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced in the brains of Alzheimer's disease patients. The downregulation of UPR signalling by PS1 mutations is caused by disturbed function of IRE1, which is the proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in neuroblastoma cells bearing PS1 mutants almost completely restores resistance to ER stress to the level of cells expressing wild-type PS1. These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.

@article{katayama1999-10587643,
  author  = {Katayama, T. and Imaizumi, K. and Sato, N. and Miyoshi, K. and Kudo, T. and Hitomi, J. and Morihara, T. and Yoneda, T. and others},
  title   = {{Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response}},
  journal = {Nature cell biology},
  year    = {1999},
  doi     = {10.1038/70265},
  pmid    = {10587643},
  url     = {https://doi.org/10.1038/70265}
}

Key findings

• These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/70265
• PubMed: 10587643
• Original source →

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