HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: fj.07-9072comv1 fj.07-9072comv2 22/3/819    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Araki, W. Articles by Tabira, T. Search for Related Content PubMed PubMed Citation Articles by Araki, W. Articles by Tabira, T.

A family of membrane proteins associated with presenilin expression and -secretase function

Wataru Araki^*,1, Noriko Takahashi-Sasaki, De-Hua Chui, Shinya Saito^*, Kazuya Takeda, Keiro Shirotani^||, Keikichi Takahashi, Kiyoko S. Murayama^*, Fuyuki Kametani^#, Hirohisa Shiraishi^**, Hiroto Komano^** and Takeshi Tabira

^* Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan;

Katayanagi Advanced Research Laboratories, Tokyo University of Technology, Hachioji, Tokyo, Japan;

Neuroscience Research Institute, Peking University, Beijing, P. R. China;

National Institute of Longevity Sciences, NCGG, Obu, Aichi, Japan;

^|| Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan;

^# Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, Setagaya, Tokyo, Japan; and

^** Faculty of Pharmaceutical Sciences, Iwate Medical University, Iwate, Japan

¹Correspondence: Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan. E-mail: araki{at}ncnp.go.jp

Presenilin 1 (PS1) forms the -secretase complex with at least three components: nicastrin, APH-1, and PEN-2. This complex mediates intramembrane cleavage of amyloid precursor protein (APP) to generate β-amyloid protein (Aβ) as well as other type 1 transmembrane proteins. Although PS1 mutations linked to familial Alzheimer’s disease influence these cleavages, their biological consequences have not been fully understood. In this study, we used mRNA differential display analysis to identify a gene, denoted adoplin-1/ORMDL-1, which displays significantly reduced expression in association with PS1 mutations. Adoplin-1 and two highly homologous genes (adoplin-2, -3) constitute a gene family that encodes transmembrane proteins. The mRNA and protein levels of adoplins (particularly adoplin-1, -2) were markedly elevated in PS-deficient fibroblasts, compared to wild-type cells. Moreover, knockdown of the three adoplins by RNA interference affected maturation of nicastrin and its association with PS1. Adoplin knockdown additionally resulted in elevated levels of APP C-terminal fragments and decreased Aβ production, suggestive of reduced -secretase activity. Our data collectively indicate that adoplins are unique molecules with PS-related expression and functions that may play important role(s) in the maturation and activity of the -secretase complex.—Araki, W., Takahashi-Sasaki, N., Chui, D.-H., Saito, S., Takeda, K., Shirotani, K., Takahashi, K., Murayama, K. S., Kametani, F., Shiraishi, H., Komano, H., Tabira, T. A family of membrane proteins associated with presenilin expression and -secretase function.

Key Words: Alzheimer’s disease • β-amyloid • nicastrin