This, and the remarkable paper from from Francis and colleagues (Dev Cell. 2002 Jul;3(1):85-97) mark real progress in the dissection of the gamma secretase complex... perhaps we are now close to knowing all it's components

View all comments by John Hardy

First of a series of papers on APH-1 and gamma cleavage in mammalian cells, following the paper from Exelixis on c.elegans and flies.

View all comments by Eddie Koo

It has only been a few months that APH-1 and PEN-2 were discovered as major players in γ-secretase function in the Notch pathway in C. elegans. Together with recent papers from Haass and Yu, the two present papers demonstrate compelling biochemical evidence that γ-secretase is a complex of four proteins: presenilin, nicastrin, PEN-2 and APH-1. The final proof, however, which would be the reconstitution of an active γ-secretase, either in vitro, or in a cell type that lacks endogenous γ-secretase activity (e.g., yeast), is still missing. The current discoveries may be useful in the design and optimization of γ-secretase inhibitors, which remain a major direction of Alzheimer's disease drug discovery despite the problems with Notch-related toxicity. A better understanding of the molecular mechanism of the γ-secretase protease complex could guide the design of drugs that influence the specificity of the protease for the different...  Read more

It has only been a few months that APH-1 and PEN-2 were discovered as major players in γ-secretase function in the Notch pathway in C. elegans. Together with recent papers from Haass and Yu, the two present papers demonstrate compelling biochemical evidence that γ-secretase is a complex of four proteins: presenilin, nicastrin, PEN-2 and APH-1. The final proof, however, which would be the reconstitution of an active γ-secretase, either in vitro, or in a cell type that lacks endogenous γ-secretase activity (e.g., yeast), is still missing. The current discoveries may be useful in the design and optimization of γ-secretase inhibitors, which remain a major direction of Alzheimer's disease drug discovery despite the problems with Notch-related toxicity. A better understanding of the molecular mechanism of the γ-secretase protease complex could guide the design of drugs that influence the specificity of the protease for the different substrates, finally leading to a drug that would inhibit AβPP cleavage but not, or to a lesser extent, the cleavage of Notch and other substrates.

View all comments by Gerard Drewes

The elegant data from both labs are quite consistent with the notion that APH-1 and PEN2 have important roles in stabilizing the PS complex and in promoting endoproteolysis. Indeed, we presented data in Orlando that fully supported these findings (our work is presently under review). There is still a bit of work to figure out where in the cell these events occur (PEN-2 appears to reside in the Golgi) and the subcellular destination/distribution of presenilin and its associated factors. Ultimately, it would be important to establish that overexpression of PS and the complex has an impact on promoting γ-secretase processing of APP-CTF, Notch S2/NEXT, or other substrates.

View all comments by Sangram Sisodia