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J. Biol. Chem., Vol. 281, Issue 43, 32240-32253, October 27, 2006

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Ubiquilin 1 Modulates Amyloid Precursor Protein Trafficking and A Secretion^*

Mikko Hiltunen¹, Alice Lu¹, Anne V. Thomas, Donna M. Romano, Minji Kim, Phill B. Jones^¶, Zhongcong Xie, Maria Z. Kounnas^||, Steven L. Wagner^||, Oksana Berezovska, Bradley T. Hyman, Giuseppina Tesco, Lars Bertram, and Rudolph E. Tanzi²

From the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the Alzheimer's Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the ^¶Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, and ^||Torrey Pines Therapeutics, Inc., La Jolla, California 92037

Ubiquilin 1 (UBQLN1) is a ubiquitin-like protein, which has been shown to play a central role in regulating the proteasomal degradation of various proteins, including the presenilins. We recently reported that DNA variants in UBQLN1 increase the risk for Alzheimer disease, by influencing expression of this gene in brain. Here we present the first assessment of the effects of UBQLN1 on the metabolism of the amyloid precursor protein (APP). For this purpose, we employed RNA interference to down-regulate UBQLN1 in a variety of neuronal and non-neuronal cell lines. We demonstrate that down-regulation of UBQLN1 accelerates the maturation and intracellular trafficking of APP, while not interfering with -, -, or -secretase levels or activity. UBQLN1 knockdown increased the ratio of APP mature/immature, increased levels of full-length APP on the cell surface, and enhanced the secretion of sAPP (- and -forms). Moreover, UBQLN1 knockdown increased levels of secreted A40 and A42. Finally, employing a fluorescence resonance energy transfer-based assay, we show that UBQLN1 and APP come into close proximity in intact cells, independently of the presence of the presenilins. Collectively, our findings suggest that UBQLN1 may normally serve as a cytoplasmic "gatekeeper" that may control APP trafficking from intracellular compartments to the cell surface. These findings suggest that changes in UBQLN1 steady-state levels affect APP trafficking and processing, thereby influencing the generation of A.

Received for publication, March 31, 2006 , and in revised form, August 8, 2006.

^* This work was supported by the Extendicare Foundation and the Finnish Academy (to M. H.), National Institutes of Health (NIH) Grant 5 P01 AG015379-08 (to B. T. H.), NIA, NIH Grant 1R01 AG023667-01 (to L. B.), Mass Alzheimer's Disease Research Center pilot Grant 218683 (to O. B.), and a research fellowship from the Deutsche Forschungsgemeinschaft (Grant 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, and Harvard Medical School, 114 16th St. C3009, Charlestown, MA 02129-4404. Tel.: 617-726-6845; Fax: 617-724-1949; E-mail: tanzi{at}helix.mgh.harvard.edu.

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