Sequence analyses of presenilin mutations linked to familial Alzheimer's disease

Don Kim Sun, Jinoh Kim

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Familial Alzheimer's disease (FAD)-linked presenilin (PS) mutations show gain-of-toxic-function characteristics. These FAD PS mutations are scattered throughout the PS molecule, reminiscent of the distribution of cystic fibrosis transmembrane conductance regulator and p53 mutations. Because of the scattered distribution of PS mutations, it is difficult to infer mechanistic insights about how these mutations cause the disease similarly. Recent careful reexamination of γ-secretase activity indicates that some PS mutations decrease the proteolytic activity of γ-secretase, suggesting a loss-of-function nature of PS mutations. To extend this observation to all known PS mutations, a large number of PS mutations were evaluated using bioinformatic tools. The analyses reveal that as many as one third of PS1 residues are highly conserved, that about 75% of FAD mutations are located to the highly conserved residues, and that most PS mutations likely damage the activity of PS. These results are consistent with the idea that the majority of PS mutations lower the activity of PS/γ-secretase.

Original languageEnglish (US)
Pages (from-to)401-412
Number of pages12
JournalCell Stress and Chaperones
Issue number4
StatePublished - Dec 2008


  • Alzheimer's disease
  • Presenilin mutations
  • Protein misfolding
  • Sequence analyses

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology


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