Deficiency of Aph1B/C-[gamma]-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-07, Vol.105 (28), p.9775
• Main Authors: Dejaegere, T, Serneels, L, Schäfer, M K, Biervliet, J Van, Horré, K, DepboyIu, C, AIvarez-Fischer, D, Herreman, A, WiIIem, M, Haass, C, Höglinger, G U, D'Hooge, R, Strooper, B De
• Format: Article
• Language: English
• Subjects: Brain; Mutation; Proteins; Psychotropic drugs; Rodents; Schizophrenia
• ISSN: 0027-8424; 1091-6490

Regulated intramembrane proteolysis by ...-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different ...-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-...-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-...-secretase. We demonstrate here that the Aph1B/C-...-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 ...-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders. (ProQuest: ... denotes formulae/symbols omitted.)