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J. Biol. Chem., Vol. 281, Issue 36, 26400-26407, September 8, 2006

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Interaction between Presenilin 1 and Ubiquilin 1 as Detected by Fluorescence Lifetime Imaging Microscopy and a High-throughput Fluorescent Plate Reader^*

Anne V. Thomas, Lauren Herl, Robert Spoelgen, Mikko Hiltunen, Phill B. Jones^¶, Rudolph E. Tanzi, Bradley T. Hyman, and Oksana Berezovska¹

From the Alzheimer's Disease Research Laboratory, Genetics and Aging Research Unit, and ^¶Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

Presenilin 1 (PS1) in its active heterodimeric form is the catalytic center of the -secretase complex, an enzymatic activity that cleaves amyloid precursor protein (APP) to produce amyloid (A). Ubiquilin 1 is a recently described PS1 interacting protein, the overexpression of which increases PS1 holoprotein levels and leads to reduced levels of functionally active PS1 heterodimer. In addition, it has been suggested that splice variants of the UBQLN1 gene are associated with an increased risk of developing Alzheimer disease (AD). However, it is still unclear whether PS1 and ubiquilin 1 interact when expressed at endogenous levels under normal physiological conditions. Here, we employ three novel fluorescence resonance energy transfer-based techniques to investigate the interaction between PS1 and ubiquilin 1 in intact cells. We consistently find that the ubiquilin 1 N terminus is in close proximity to several epitopes on PS1. We show that ubiquilin 1 interacts both with PS1 holoprotein and heterodimer and that the interaction between PS1 and ubiquilin 1 takes place near the cell surface. Furthermore, we show that the PS1-ubiquilin 1 interaction can be detected between endogenous proteins in primary neurons in vitro as well as in brain tissue of healthy controls and Alzheimer disease patients, providing evidence of its physiological relevance.

Received for publication, February 3, 2006 , and in revised form, June 26, 2006.

^* This work was supported by National Institutes of Health Grant 5 P01 AG015379-08 (to B. T. H.), Mass Alzheimer Disease Research Center pilot Grant 218683 (to O. B.), National Institute of Mental Health, National Institutes of Health NIA, and the Extendicare Foundation (to M. H. and R. E. T.), and Deutsche Forschungsgemeinschaft Research Fellowship TH 1129/1-1 (to A. V. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neurology/Alzheimer Unit, 114 16th St., Charlestown, MA 02129. Tel.: 617-726-2299; Fax: 617-724-1480; E-mail: oberezovska{at}partners.org.

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