Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment
Abstract
Regulated intramembrane proteolysis by γ-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different γ-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-γ-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-γ-secretase. We demonstrate here that the Aph1B/C-γ-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 γ-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- July 2008
- DOI:
- 10.1073/pnas.0800507105
- Bibcode:
- 2008PNAS..105.9775D
- Keywords:
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- Alzheimer's;
- knockout;
- schizophrenia;
- presenilin;
- prepulse inhibition;
- Biological Sciences:Neuroscience