Title: Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating which can be reversed with antipsychotic treatment
Authors: Dejaegere, Tim
Serneels, Lutgarde
Schaefer, M. K
Van Biervliet, Jerome
Horré, Katrien
Depboylu, C
Alvarez-Fischer, D
Herreman, An
Willem, M
Haass, C
Hoeglinger, G. U
D'Hooge, Rudi
De Strooper, Bart # ×
Issue Date: 15-Jul-2008
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:105 issue:28 pages:9775-9780
Abstract: Regulated intramembrane proteolysis by gamma-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different gamma-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-gamma-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-gamma-secretase. We demonstrate here that the Aph1B/C-gamma-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of Aph1BC(-/-) mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects gamma-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
Laboratory for Biological Psychology
Laboratory for the Research of Neurodegenerative Diseases
Laboratory of Molecular Biology of Leukemia
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Dejaegere et al_PNAS.pdf Published 1062KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science