Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment
Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment
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DOI：
10.1073/pnas.0800507105
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发表时间：
2008-07-15
影响因子：
11.1
通讯作者：
De Strooper, B.
中科院分区：
文献类型：
--
作者：
Dejaegere, T.;Serneels, L.;De Strooper, B.
由γ-分泌酶调节的膜内蛋白水解在其跨膜结构域切割蛋白质，并参与重要的信号传导途径。至少有四种不同的γ-分泌酶复合物已被确定，但很少有人知道他们的生物学作用和特异性。以前的工作已经证明了Aph 1A-γ-分泌酶复合物参与Notch信号传导，但没有特定的功能可以分配给Aph 1B/C-γ-分泌酶。我们在这里证明，Aph 1B/C-γ-分泌酶复合物在与精神分裂症发病机制相关的脑区中表达，Aph 1B/C缺乏会导致药理学和行为异常，这些异常可以通过抗精神病药物逆转。在分子水平上，我们发现Nrg 1片段在Aph 1BC（-/-）小鼠的脑中积累。我们的观察获得了临床相关性的证明，在Nrg 1跨膜结构域的Val-亮氨酸突变，与精神分裂症的风险增加，影响γ-分泌酶切割Nrg 1。这一发现表明，Nrg 1的膜内蛋白水解失调可能会增加精神分裂症和相关疾病的风险。
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.