Gamma-Secretase and Myelin: A Paradigm Shift in Brain Disorders

描述（由申请人提供）：γ-分泌酶是一种由四种蛋白（早老素、nicastrin、Aph-1和Pen-2）组成的膜结合复合物，可切割多种底物。γ-分泌酶是控制几种重要生化和细胞通路的关键信号分子。当有缺陷时，它与阿尔茨海默病和其他人类疾病有遗传和致病关系。γ-分泌酶对淀粉样蛋白前体蛋白的切割产生神经毒性的β-淀粉样肽，这种肽构成了阿尔茨海默病患者大脑中的标志性斑块。γ-分泌酶切割Notch调节细胞命运，包括分化、增殖和存活，因此与多种人类疾病有关。ErbB4的断裂调节神经元的髓鞘形成，ErbB4介导的信号通路与精神分裂症有关。这一提议询问少突胶质细胞γ-分泌酶活性的丧失是否有助于与神经功能障碍一致的行为改变。大脑中只有大约10%是神经元。胶质细胞占剩余的90%，其中少突胶质细胞占大多数。在发育和损伤期间，少突胶质细胞围绕神经元轴突形成致密髓鞘，髓鞘是一种脂肪膜，保护和滋养神经元，促进神经电位在神经元之间的快速传导。神经生物学传统上专注于研究神经元，以及为什么神经元在神经精神和神经退行性疾病中丧失功能和死亡。然而，本项目分析了γ-分泌酶如何促进髓鞘形成，以及髓鞘形成缺陷是否单独导致各种脑部疾病中所见的神经功能障碍。特异性Aim 1询问小鼠少突胶质细胞缺乏nicastrin是否表现出与神经功能障碍一致的行为。该目的还询问少突胶质细胞中早老素的丢失是否表现出类似的行为。将测试几种精神药物是否有能力逆转这些行为变化。特异性目的2询问少突胶质细胞中nicastrin的缺失是否会导致这些细胞髓鞘化目标轴突的能力发生变化。髓鞘形成的变化将在体内（在动物模型的大脑中）和体外（在少突胶质细胞-神经元共培养系统中）进行检查。特异性目的3询问少突胶质细胞中nicastrin的缺失会影响哪些细胞信号通路。本文将分析小鼠模型和共培养系统中最重要和最相关的γ-分泌酶底物Notch、ErbB4和APP。总之，本文描述的实验将阐明γ-分泌酶在调节髓鞘形成中的作用，并回答少突胶质细胞γ-分泌酶如何促进对行为至关重要的神经网络的完整性。因此，这项工作代表了一种思考大脑功能和疾病的新方式。

DESCRIPTION (provided by applicant): γ-secretase is a membrane-bound complex of four proteins - presenilin, nicastrin, Aph-1, and Pen-2 - that cleaves a wide variety of substrates. γ-secretase is a key signal molecule that controls several essential biochemical and cellular pathways. When defective, it is genetically and causatively linked to Alzheimer's disease and other human disorders. Cleavage of the amyloid precursor protein by γ-secretase produces the neurotoxic β-amyloid peptides that comprise the hallmark plaques found in the brains of Alzheimer's patients. Cleavage of Notch by γ-secretase regulates cell fate, including differentiation, proliferation, and survival, and has thus been implicated in multiple human diseases. Cleavage of ErbB4 regulates the myelination of neurons and ErbB4-mediated signaling pathway is linked to schizophrenia. This proposal asks whether loss of γ-secretase activity in oligodendrocytes contributes to behavioral changes consistent with neural dysfunctions. Only approximately 10 percent of the brain is neurons by mass. Glial cells comprise the remaining 90 percent, of which oligodendrocytes comprise the majority. During development and upon injury, oligodendrocytes surround the axons of neurons to form compact myelin, a fatty membrane that protects and nourishes neurons and facilitates the rapid conductance of nerve potentials from neuron to neuron. Neurobiology has traditionally focused on studying neurons, and on why neurons become defunct and die in neuropsychiatric and neurodegenerative disorders. This project, however, analyzes how γ-secretase contributes to myelination and whether defects in myelination alone contribute to the neural dysfunctions seen in various brain diseases. Specific Aim 1 asks whether mice that lack nicastrin in oligodendrocytes exhibit behaviors consistent with neural dysfunctions. This aim also asks whether loss of presenilin from oligodendrocytes exhibits similar behaviors. Several psychoactive drugs will be tested for their ability to reverse these behavioral changes. Specific Aim 2 asks whether the loss of nicastrin from oligodendrocytes results in changes in the ability of these cells to myelinate their target axons. Changes in myelination will be examined both in vivo (in the brains of animal model) and in vitro (in an oligodendrocyte-neuron co-culture system). Specific Aim 3 asks what cellular signaling pathways are affected by loss of nicastrin in oligodendrocytes. Here, the most important and relevant γ-secretase substrates, Notch, ErbB4, and APP, will be analyzed in the mouse model and the co- culture system. Together, the experiments described herein will elucidate γ-secretase's role in regulating myelination and answer how oligodendrocyte γ-secretase contributes to the integrity of neural networks crucial for behaviors. As such this work represents a new way of thinking about brain functions and disorders.