In Alzheimer's disease, the processing of the amyloidβ precursor protein (AβPP) to yield the amyloidogenic Aβ42 peptide is mediated by the intramembrane proteolytic activity of γ-secretase, making this protease a potential target for drug development. One impediment to such a strategy, however, is that the protease is also involved in the processing of notch, a membrane receptor and signal transduction molecule, which, when activated, regulates many intracellular pathways and has a profound impact on cell differentiation.
In yesterday's PNAS online, researchers from the University of Toronto and New York University School of Medicine, report that mutations in the γ-secretase-associated protein, nicastrin, can lead to a selective enhancement of notch processing. This finding suggests that the proteolytic cleavage of AβPP and notch may be independently regulated, and offers hope that specific inhibitors of the AβPP pathway can be developed.
First author Richard Rozmahel, working with Peter St. George-Hyslop and colleagues, discovered the selective activation of notch in presenilin 1 (PS1) null mice that had been crossed with wild-type animals. Presenilin 1 and γ-secretase are considered by many to be one and the same (see related news items 1, 2, and 3). PS1 null mice typically have severe deformities that correlate with a lack of notch processing. However, some of the offspring of the cross had a much milder phenotype and notch processing was increased to about 43 percent that of wild-type levels-notch processing in PS1 nulls is about 34 percent that of wild type. AβPP processing, on the other hand, didn't seem to be affected, as determined by western blotting and ELISA measurements of brain Aβ40 and Aβ42.
The researchers mapped the locus responsible for the rescue to a narrow region of chromosome 1 on some of the wild-type mice. This region contains two strong candidates that could be responsible for the rescue, presenilin 2 and nicastrin. DNA sequence analysis showed that the partially rescued mice hade no changes in the PS2 coding region, nor in PS2 protein levels. The authors did find two missense mutations in the nicastrin gene. One of these (phenylalanine 21 to serine) occurs in the N-terminal hydrophobic region, and could be part of a signal peptide or a membrane-associated domain, the other (isoleucine 678 to threonine) occurs within the transmembrane domain. The authors predict that either of these mutations could subtly alter interactions between nicastrin and other partners in the γ-secretase complex.—Tom Fagan
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- Rozmahel R, Mount HT, Chen F, Nguyen V, Huang J, Erdebil S, Liauw J, Yu G, Hasegawa H, Gu Y, Song YQ, Schmidt SD, Nixon RA, Mathews PM, Bergeron C, Fraser P, Westaway D, St George-Hyslop P. Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14452-7. PubMed.