Nature Medicine
5, 164 - 169 (1999)
doi:10.1038/5526
Presenilin mutations associated with Alzheimer disease cause defective
intracellular trafficking of  -catenin,a component of the
presenilin protein complexM. Nishimura1, 5, G. Yu1, 5, G. Levesque1, 5, D.M. Zhang1, 5, L. Ruel2, F. Chen1, P. Milman1, E. Holmes1, Y. Liang1, T. Kawarai1, E. Jo1, A. Supala1, E. Rogaeva1, D -M. Xu1, C. Janus1, L. Levesque1, Q. Bi1, M. Duthie1, R. Rozmahel3, K. Mattila4, L. Lannfelt4, D. Westaway1, H.T.J. Mount1, J. Woodgett2, P.E. Fraser1
& P. St George−Hyslop11
Centre for Research in Neurodegenerative Diseases,
Departments of Medicine (Neurology), Medical Biophysics, Pathology, and Pharmacology,
University of Toronto, 6 Queen's Park Crescent West,
Toronto, Ontario, Canada M5S 3H2; and
Department of Medicine (Division of Neurology), The Toronto Hospital,
395 Bathurst Street, Toronto, Ontario,
Canada, M5S 3H2
2
Ontario Cancer Institute, Dept of Medical Biophysics
and Experimental Therapeutics, University of Toronto, 610 University
Avenue, Toronto, Ontario, Canada,
M5G 2M9
3
Department of Pharmacology, University of Toronto,
and Department of Genetics, The Hospital for Sick Children,
555 University Avenue, Toronto
4
Karolinska Institutet, Department of Clinical Neuroscience
and Family Medicine, Novum, KFC, Huddinge Hospital, 141 86
Huddinge, Sweden
5
M.N., G.Y., G.L. & D.M.Z. contributed equally to this
study
Correspondence should be addressed to P. St George−Hyslop p.hyslop@utoronto.caThe presenilin proteins are components of high−molecular−weight
protein complexes in the endoplasmic reticulum and Golgi apparatus that also
contain  -catenin. We report here that presenilin mutations associated
with familial Alzheimer disease (but not the non−pathogenic Glu318Gly
polymorphism) alter the intracellular trafficking of -catenin after
activation of the Wnt/-catenin signal transduction pathway. As with
their effect on APP processing, the effect of PS1 mutations on trafficking
of -catenin arises from a dominant 'gain of aberrant function' activity.
These results indicate that mistrafficking of selected presenilin ligands
is a candidate mechanism for the genesis of Alzheimer disease associated with
presenilin mutations, and that dysfunction in the presenilin−-catenin
protein complexes is central to this process.
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