Characterizing novel adult neuronal survival factors

描述（由申请人提供）：神经元的功能和活力通常依赖于分泌的生长因子。虽然在发育中的神经系统中最广泛地研究，但神经营养因子在成人脑中是重要的，并且已被检查为成人神经退行性疾病的治疗方式。因此，在成人脑中分离具有神经营养活性的蛋白质可能对我们理解成熟神经系统中神经元完整性和功能的维持以及作为一系列神经和精神疾病的潜在治疗剂具有广泛的意义。 我们鉴定了一个脑特异性蛋白质家族（Cbln 1-Cbln 4），称为突触营养蛋白，具有成人神经营养因子的特性。Cbln 1和Cbln 3是分泌的糖蛋白，在成熟小脑颗粒细胞中共表达，并形成结构上与肿瘤坏死因子-α（TNF α）相关的三聚体复合物。在小鼠中通过同源重组消除Cbln 1导致共济失调、颗粒细胞-浦肯野细胞突触相互作用中的显著结构和生理缺陷以及成年小脑颗粒神经元的进行性变性。因此，Cbln 1是一类新型因子的原型，其调节突触稳定性和功能以及神经元存活。值得注意的是，浦肯野细胞中孤儿谷氨酸δ 2受体（GluRdelta 2）的缺失模拟了cbln 1缺失小鼠的表型。因此，突触前Cbln 1和突触后GluRdelta 2可能是一种新的营养信号通路的组成部分。这种机制可能存在于大脑的其他地方，对人类的神经精神疾病（突触传递中断）和神经退行性疾病（神经元损失和功能障碍）有影响。 在本申请中，我们利用TNF α和GluRdelta 2的结构和功能特性来阐明cbln 1基因敲除小鼠神经缺陷的分子基础，并表征Cbln 1信号通路的组成部分。

DESCRIPTION (provided by applicant): The function and viability of neurons is frequently dependent upon secreted growth factors. Although most extensively investigated in the developing nervous system neurotrophic factors are important in the adult brain and have been examined as therapeutic modalities in adult neurodegenerative conditions. Therefore, the isolation of proteins in adult brain with neurotrophic activity could have broad implications both for our understanding of the maintenance of neuronal integrity and function in the mature nervous system and as potential therapeutic agents for a range of neurological and psychiatric disorders. We identified a family of brain-specific proteins (Cbln1-Cbln4), termed synaptotrophins that have properties of adult neurotrophic factors. Cbln1 and Cbln3 are secreted glycoproteins that are co-expressed in mature cerebellar granule cells and form trimeric complexes that are structurally related to tumor necrosis factor-alpha (TNFalpha). Elimination of Cbln1 through homologous recombination in mice causes ataxia, marked structural and physiological defects in granule celI-Purkinje cell synaptic interactions and the progressive degeneration of adult cerebellar granule neurons. Thus Cbln1 is the prototype of a novel class of factor that regulates synaptic stability and function and neuronal survival. Remarkably, loss of the orphan glutamate delta2 receptor (GluRdelta2) in Purkinje cells mimics the phenotype of the cbln1-null mouse. Thus, presynaptic Cbln1 and postsynaptic GluRdelta2 may be components of a novel trophic signaling pathway. This mechanism likely exists elsewhere in brain having implications for neuropsychiatric (disrupted synaptic transmission) and neurodegenerative disorders (neuronal loss and functional impairment) in man. In this application we take advantage of the structural and functional properties of TNFalpha and GluRdelta2 to elucidate the molecular bases of the neural deficits in cbln1-null mice and characterize the components of the Cbln1 signaling pathway.