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

作者：Dejaegere T; Serneels L; Schaefer M K; Van Biervliet J; Horre K; Depboylu C; Alvarez Fischer D; Herreman A; Willem M; Haass C; Hoeglinger G U; D'Hooge R; De Strooper B^*

来源：Proceedings of the National Academy of Sciences, 2008, 105(28): 9775-9780.

DOI：10.1073/pnas.0800507105

• Alzheimer's
• knockout
• schizophrenia
• presenilin
• prepulse inhibition

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.

• 出版日期2008-7-15