Mutation of conserved aspartates affect maturation of presenilin 1 and presenilin 2 complexes

G. Yu, F. Chen, M. Nishimura, H. Steiner, A. Tandon, T. Kawarai, S. Arawaka, A. Supala, Y. Q. Song, E. Rogaeva, E. Holmes, D. M. Zhang, P. Milman, P. Fraser, C. Haass, P. St George-Hyslop

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Presenilin (PS1 and PS2) holoproteins are transiently incorporated into low molecular weight (MW) complexes. During subsequent incorporation into a higher MW complex, they undergo endoproteolysis to generate stable N- and C-terminal fragments (NTF/CTF). Mutation of either of two conserved aspartate residues in transmembrane domains inhibits both presenilin-endoproteolysis and the proteolytic processing of APP and Notch. We show that aspartate-mutant holoprotein presenilins are not incorporated into the high molecular weight, NTF/CTF-containing complexes. Aspartate-mutant presenilin holo-proteins also preclude entry of endogenous wild-type PS1/PS2 into the high molecular weight complexes, but do not affect the incorporation of wild-type holoproteins into lower molecular weight holoprotein complexes. These data suggest that the loss-of-function aspartate-mutants cause altered PS complex maturation, and argue that the functional presenilin moieties are contained in the high molecular weight presenilin NTF/CTF-containing complexes.

Original languageEnglish (US)
Pages (from-to)6-11
Number of pages6
JournalActa Neurologica Scandinavica, Supplement
Issue number176
StatePublished - Dec 1 2000


  • Alzheimer disease
  • Amyloid β-peptide
  • Presenilin complexes
  • γ-secretase

ASJC Scopus subject areas

  • Medicine(all)


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