. Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. PubMed.

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  1. This work is a strong support for the central role of Aβ peptide in the causation of familial Alzheimer’s Disease (FAD) in the PSEN families. Indeed the novel mutations described here are the first examples that cause complete haploinsufficiency of PSEN. This is in contrast to the classical FAD-PSEN mutations, which are causing partial loss of function. Complete loss of function should interfere strongly with Notch signaling, but will at the same time lower all forms of Aβ generation. I would therefore predict that such patients are actually protected against AD, and it is very exciting to read that they indeed do not show any symptoms of dementia. The skin abnormalities of these patients are, in contrast, completely compatible with loss of Notch signaling.

    The observations in this paper support Mike Wolfe’s and my proposal of some years ago that the FAD mutations cause AD by “partial loss of proteolysis function” (De Strooper, 2007; Wolfe, 2007; see also DeStrooper/Davies Live Discussion, Shen/Kelleher Live Discussion). The PSEN mutations associated with FAD have indeed a qualitative effect: they only decrease the efficiency of the γ-secretase, which results in a relative shift of the Abeta profiles to longer Aβ peptides. Therefore, and although they are also loss–of-function mutations, the PSEN-FAD mutations cause AD, while the novel acne inversa mutations, which block all Aβ generation, do not.

    It is also very significant that in the acne inversa patients, mutations were described in three of the four gamma-secretase subunits, while in FAD patients mutations are observed only in the catalytic PSEN subunit. The latter are always missense mutations, causing single amino acid substitutions in most of the cases. This indicates that partial functionality of the γ-secretase is needed to cause AD.

    In conclusion: I consider this paper as very interesting evidence in favor of the hypothesis that only partial loss-of-function mutations of PSEN1&2 can cause FAD and that they necessarily operate via changing the Aβ profiles (see Bentahir et al., 2006; De Strooper, 2007; Kuperstein et al., 2010). Deficiency of the Notch or other signaling pathways regulated by γ-secretase is thus clearly not sufficient to cause AD.

    References:

    . Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):141-6. PubMed.

    . When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):136-40. PubMed.

    . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.

    . Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb;8(2):141-6. PubMed.

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