γ-Secretase and Human Disease

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Science  19 Nov 2010:
Vol. 330, Issue 6007, pp. 1055-1056
DOI: 10.1126/science.1198668

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The suspected culprit in Alzheimer's disease has been γ-secretase, an enzyme that cleaves type 1 transmembrane proteins. It processes amyloid precursor protein (APP), generating the β-amyloid (Aβ) peptides that give rise to the characteristic brain plaques of Alzheimer's disease patients. Presenilin is the presumptive catalytic subunit of γ-secretase, and mutations in the PSEN1 and PSEN2 genes that encode this subunit are the most common cause of familial Alzheimer's disease. On page 1065 of this issue, Wang et al. (1) report that mutations in PSEN1 are also associated with a severe skin disorder, acne inversa. Mutations in genes encoding two other subunits of γ-secretase are also linked to this severe skin condition. The finding raises questions about the function of γ-secretase in human diseases, with implications for the development of therapeutics.