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Originally published In Press as doi:10.1074/jbc.M909624199 on March 21, 2000

J. Biol. Chem., Vol. 275, Issue 22, 17136-17142, June 2, 2000
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The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Abeta 42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants*

Carlos A. SauraDagger , Taisuke Tomita§, Salvador Soriano, Masaaki Takahashi||, Jae-Yoon LeemDagger , Toshiyuki Honda**, Edward H. Koo, Takeshi Iwatsubo§, and Gopal ThinakaranDagger Dagger Dagger

From the Dagger  Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, the § Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan, the  Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, the || Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the ** Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan

Presenilin 1 (PS1) and presenilin 2 (PS2) are polytopic membrane proteins that are mutated in the majority of early onset familial Alzheimer's disease (FAD) cases. Two lines of evidence establish a critical role for PS in the production of beta -amyloid peptides (Abeta ). FAD-linked PS mutations elevate the levels of highly amyloidogenic Abeta ending at residue 42 (Abeta 42), and cells with ablated PS1 alleles secrete low levels of Abeta . Several recent reports have shown that the hydrophilic loop (HL) domain, located between transmembrane domains 6 and 7, contains sites for phosphorylation, caspase cleavage, and sequences that bind several PS-interacting proteins. In the present report, we examined the metabolism of PS polypeptides lacking the HL domain and the influence of these molecules on Abeta production. We report that the deletion of the HL domain does not have a deleterious effect on the regulated endoproteolysis of PS, saturable accumulation of PS fragments, or the self-association of PS fragments. Abeta production was not significantly altered in cells expressing HL-deleted PS polypeptides compared with cells expressing full-length PS. Importantly, deletion of the HL domain did not affect FAD mutation-mediated elevation in the production of Abeta 42. Furthermore, the deletion of the HL domain did not impair the role of PS1 or PS2 in facilitating Notch processing. Thus, our results argue against a biologically or pathologically relevant role for the HL domain phosphorylation and caspase cleavage and the association of PS HL domain-interacting proteins, in amyloid precursor protein metabolism and Abeta production or Notch cleavage.

* This work was supported by the United States Public Health Service, National Institutes of Health Grants 1PO1 AG14248 (to G. T.) and NS28121 (to E. H. K.), the Alzheimer's Association (to G. T.), the Adler Foundation (to G. T. and C. A. S.), the Brain Research Foundation (to G. T.), an award to the University of Chicago's Division of Biological Sciences under the Research Resources Program for Medical Schools of the Howard Hughes Medical Institute (G. T.), and grants-in-aid from the Ministry of Health and Welfare, the Ministry of Education, Science, Culture, and Sports, Japan, and CREST of Japan Science and Technology Corporation (to T. I.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger To whom correspondence should be addressed: Dept. of Neurobiology, Pharmacology and Physiology, University of Chicago, Knapp Research Center R212, 924 E. 57th St., Chicago, IL 60637. Tel.: 773-834-3752; Fax: 773-834-3808; E-mail: Gopal@uchicago.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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