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

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.

authors

Dejaegere T,Serneels L,Schäfer MK,Van Biervliet J,Horré K,Depboylu C,Alvarez-Fischer D,Herreman A,Willem M,Haass C,Höglinger GU,D'Hooge R,De Strooper B

doi

10.1073/pnas.0800507105

subject

Has Abstract

pub_date

2008-07-15 00:00:00

pages

9775-80

issue

28

eissn

0027-8424

issn

1091-6490

pii

0800507105

journal_volume

105

pub_type

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