2008-7-16 17:24:08

PNAS：特殊蛋白缺乏与精神分裂症有关

佚名

精神分裂症是一种复杂的神经疾病，它影响着大约1%的人口。尽管已知大脑的前额叶皮层和海马区与该病有关，科学家对于引发该病的生物化学根源知之甚少。与精神分裂症发生风险高有关的一个蛋白质是Neuregulin-1（Nrg1），它在神经系统的发育和功能方面扮演着一个至关重要的角色。相关论文发表在美国《国家科学院院刊》（PNAS）上。

此前的研究表明精神分裂症患者的Nrg-1信号传导中断。Tim Dejaegere及其同事证明了缺少Aph1B/C-伽玛-分泌酶——它在本质上是一种分子剪刀，可以把Nrg-1剪切成正确的长度——可能在小鼠中引发类精神分裂症的症状。这组科学家证明了缺乏这种化合物会导致小鼠出现类似于人类精神分裂症患者出现的症状，并发现了此类药理学的和行为的异常可以通过针对这种分泌酶的抗精神病药物加以逆转。这组作者提出Nrg1过程的调控不良可能会增加精神分裂症的风险，而且这在其他相关疾病中可能也有意义。（生物谷Bioon.com）

生物谷推荐原始出处：

PNAS，vol. 105 no. 28 9775-9780，T. Dejaegere，B. De Strooper

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

T. Dejaegere*,^†, L. Serneels*,^†, M. K. Schäfer^‡, J. Van Biervliet*,^†, K. Horré*,^†, C. Depboylu^§, D. Alvarez-Fischer^§, A. Herreman*,^†, M. Willem^¶, C. Haass^¶, G. U. Höglinger^§, R. D'Hooge^‖, and B. De Strooper*,^†,**

+Author Affiliations

*Department of Molecular and Developmental Genetics, Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium;
^†Center for Human Genetics, and
^‖Laboratory of Biological Psychology, Department of Psychology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;
^‡Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, and
^§Department of Experimental Neurology, Philipps University, 35033 Marburg, Germany; and
^¶Adolf Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany

Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 11, 2008 (received for review January 17, 2008)

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.