The identity of substrates of γ-secretase is becoming more and more interesting—although the wealth of putative candidate substrates is also becoming somewhat disturbing. Scrutinizing all of them to define the exact physiological role (if any) of the processing of the "snipped-off" pieces of proteins will be a daunting task, but it is a "must" to understand their contributions to physiology and pathophysiology.

It is surprising and even hard to believe that on the growing list of substrates (who keeps track?), only APP and the amyloid peptides are "offensive" substrates of mutant PS1 in causing early-onset familial AD. Since even these most aggressive forms of FAD take decades to develop, one wonders why no other problems or diseases are associated with mutant PS1?

As indicated rightfully by Gabrielle Strobel, the "gain- or loss-of-function" debate surrounding mutant PS1/γ-secretase will hopefully soon and finally be settled as a "gain- and loss-of-function" problem, i.e., gain as a proteinase by producing more Aβ42 and loss as a calcium ion regulating entity. This...  Read more

The identity of substrates of γ-secretase is becoming more and more interesting—although the wealth of putative candidate substrates is also becoming somewhat disturbing. Scrutinizing all of them to define the exact physiological role (if any) of the processing of the "snipped-off" pieces of proteins will be a daunting task, but it is a "must" to understand their contributions to physiology and pathophysiology.

It is surprising and even hard to believe that on the growing list of substrates (who keeps track?), only APP and the amyloid peptides are "offensive" substrates of mutant PS1 in causing early-onset familial AD. Since even these most aggressive forms of FAD take decades to develop, one wonders why no other problems or diseases are associated with mutant PS1?

As indicated rightfully by Gabrielle Strobel, the "gain- or loss-of-function" debate surrounding mutant PS1/γ-secretase will hopefully soon and finally be settled as a "gain- and loss-of-function" problem, i.e., gain as a proteinase by producing more Aβ42 and loss as a calcium ion regulating entity. This function is proposed to operate at synapses, although we do not understand how it is exerted and controlled.

I remember as recently as in Philadelphia, and at previous meetings and in seminars, the skepsis when we tried to convey these notions. One cannot help but muse over the slow learning and fast forgetting in the AD-field.

References:
Dewachter I, Van Leuven F. Secretases as targets for the treatment of Alzheimer's disease: the prospects. Lancet Neurol. 2002 Nov;1(7):409-16. Review. Abstract

Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, Van Leuven F. Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein. J Biol Chem. 2003 Jan 24;278(4):2484-9. Epub 2002 Nov 12. Abstract

Ris L, Dewachter I, Reverse D, Godaux E, Van Leuven F. Capacitative calcium entry induces hippocampal long term potentiation in the absence of presenilin-1. J Biol Chem. 2003 Nov 7;278(45):44393-9. Epub 2003 Aug 05. Abstract

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