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Hyperaccumulation of Fad-Linked Presenilin 1 Variants in Vivo

  1. Author:
    Lee, M. K.
    Borchelt, D. R.
    Kim, G.
    Thinakaran, G.
    Slunt, H. H.
    Ratovitski, T.
    Martin, L. J.
    Kittur, A.
    Gandy, S.
    Levey, A. I.
    Jenkins, N.
    Copeland, N.
    Price, D. L.
    Sisodia, S. S.

  2. Author Address

    Lee MK JOHNS HOPKINS UNIV SCH MED DEPT PATHOL 558 ROSS BLDG 720 RUTLAND AVE BALTIMORE, MD 21205 USA JOHNS HOPKINS UNIV SCH MED DEPT NEUROL BALTIMORE, MD 21205 USA JOHNS HOPKINS UNIV SCH MED DEPT NEUROSCI BALTIMORE, MD 21205 USA CORNELL UNIV COLL MED NEW YORK, NY 10021 USA EMORY UNIV DEPT NEUROL ATLANTA, GA 30322 USA NCI FREDERICK CANC RES & DEV CTR MAMMALIAN GENET LAB ABL BASIC RES PROGRAM FREDERICK, MD 21702 USA
    1. Year: 1997
  2. Journal: Nature Medicine
    1. 3
    2. 7
    3. Pages: 756-760
  4. Type of Article: Article
  1. Abstract:

    Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes can cause Alzheimer's disease in affected members of the majority of early-onset familiar Alzheimer's disease (FAD) pedigrees(1-7). PS1 encodes an ubiquitously expressed, eight transmembrane protein(1,8-11). PS1 is endoproteolytically processed to an aminoterminal derivative (similar to 27-28 kDa) and a carboxy-terminal derivative (similar to 17-18 kDa). These polypeptides accumulate to saturable levels in the brains of transgenic mice, independent of the expression of PS1 holoprotein(12). We now document that, in the brains of transgenic mice, the absolute amounts of accumulated N- and C-terminal derivatives generated from the FAD-linked PS1 variants in which Glu replaces Ala at codon 246 (A246E) or Leu replaces Met at codon 146 (M146L) accumulate to a significantly higher degree (similar to 40-50%) than the fragments derived from wild-type PS1. Moreover, the FAD-linked Delta E9 PS1 variant, a polypeptide that is not subject to endoproteolytic cleavage in vivo, also accumulates in greater amounts than the fragments generated from wild-type human PS1. Thus, the metabolism of PS1 variants linked to FAD is fundamentally different from that of wild-type PS1 in vivo. [References: 20]

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