1Proc. Natl. Acad. Sci. U.S.A. 2008 Jul 105: 9775-80
TitleDeficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment.
AbstractRegulated 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.
SCZ Keywordsschizophrenia
2Elife 2014 -1 3: -1
TitleCell autonomous regulation of hippocampal circuitry via Aph1b-?-secretase/neuregulin 1 signalling.
AbstractNeuregulin 1 (NRG1) and the ?-secretase subunit APH1B have been previously implicated as genetic risk factors for schizophrenia and schizophrenia relevant deficits have been observed in rodent models with loss of function mutations in either gene. Here we show that the APH1B-?-secretase is selectively involved in Nrg1 intracellular signalling. We found that APH1B-deficient mice display a decrease in excitatory synaptic markers. Electrophysiological recordings show that APH1B is required for excitatory synaptic transmission and plasticity. Furthermore, gain and loss of function and genetic rescue experiments indicate that Nrg1 intracellular signalling promotes dendritic spine formation downstream of APH1B-?-secretase in vitro and in vivo. In conclusion, our study sheds light on the physiological role of APH1B-?-secretase in brain and provides a new mechanistic perspective on the relevance of NRG1 processing in schizophrenia.
SCZ Keywordsschizophrenia