A paper in the current PNAS is advancing the controversy over the identity of the catalytic subunit of γ-secretase, the protease responsible for the cleavage of AβPP and the generation of Aβ variants Aβ40 and Aβ42. While the evidence is inconclusive, many researchers consider presenilin-1 (PS1), mutations of which cause familial Alzheimer's disease, to be the prime candidate for this catalytic role (see related news item). Detractors point to numerous inconsistencies in the data, including that PS1 and the γ-secretase proteolytic activity are localized to different cellular compartments, and the finding that overexpression of inactive, mutant PS1 fails to affect production of Aβ. Proponents point to the presence of endogenous active PS1 as a complicating factor in these transfection experiments.
This latter issue is now being addressed by Hui Zheng, Baylor College of Medicine, Houston, with colleagues at RIKEN and Gunma University, Japan, and elsewhere. The authors have expressed mutant human PS1 in presenilin knockout mice, eliminating any contribution by endogenous protein. Their work appears in next week's PNAS and is currently available online.
Xuefeng Xia et al. found that mutating one of the proposed essential aspartic acid residues of PS1 to alanine (D257A) has profound consequences. D257A mutants failed to rescue PS knockout mice, which die shortly before or after birth due to developmental defects. Cultured primary neurons from these animals failed to process AβPP as judged by the profound decrease in Aβ40 and Aβ42 production. Normal development and AβPP processing was rescued, however, when the authors instead used a presenilin construct that misses amino acids 340-371, the binding loop for one putative binding partner of PS1, β-catenin. This experiment suggests not only that PS1 is essential for γ-secretase activity, but that normal AβPP processing can proceed in the absence of any interaction with β-catenin.—Tom Fagan
- Xia X, Wang P, Sun X, Soriano S, Shum WK, Yamaguchi H, Trumbauer ME, Takashima A, Koo EH, Zheng H. The aspartate-257 of presenilin 1 is indispensable for mouse development and production of beta-amyloid peptides through beta-catenin-independent mechanisms. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8760-5. PubMed.