Activation of Plp gene expression in oligodendrocytes

描述（由申请人提供）：髓磷脂是由中枢神经系统的少突胶质细胞产生的，它在沿轴突传播动作电位中的作用已经得到了很好的研究。髓磷脂是神经胶质细胞质膜的延伸，但它在生物化学上有很大的不同。这种差异的部分原因可以归结为专门针对髓鞘膜的蛋白质的组成。其中一种蛋白质，髓磷脂蛋白脂蛋白（PLP）几乎占成人中枢神经系统髓磷脂总蛋白的50%。这种基因的表达受到严格调控。在人类中，P/ P基因（位于X染色体上）的突变已被证明与X连锁髓鞘异常疾病Pelizaeus-Merzbacher病（PMD）和某些类型的痉挛性截瘫（SPG-2）有关。髓鞘发育障碍可由P/ P基因表达水平升高或缺乏表达引起。因此，P/ P的准确表达是至关重要的，阐明其调控将有助于破译一些PMD/SPG-2患者可能发生突变的基本转录调控元件。另一方面，阐明该基因受调控的机制可以为PMD/SPG-2的其他原因提供见解，这些原因不是由P/ P基因突变引起的。

DESCRIPTION (provided by applicant): Myelin is produced by oligodendrocytes in the CNS, and its role in propagation of the action potential along the axon has been well studied. Myelin is an extension of the glial cell's plasma membrane, however it is biochemically very different. Part of this difference can be attributed to the composition of the proteins specifically targeted to the myelin membrane. One of these proteins, the myelin proteolipid protein (PLP) accounts for almost 50% of the total protein found in adult CNS myelin. Expression of the gene is tightly regulated. In humans, mutations in the P/p gene (which resides on the X chromosome) have been shown to be associated the X-linked dysmyelinating disorder Pelizaeus-Merzbacher disease (PMD), and some types of spastic paraplegia (SPG-2). Dysmyelination can arise from either elevated levels of P/p gene expression or lack of expression. Thus accurate expression of the P/p is critical, and elucidation of its regulation will be helpful in deciphering essential transcription regulatory elements that may be mutated in some people with PMD/SPG-2. On the other hand, elucidation of the mechanisms whereby the gene is regulated could provide insight into alternative causes of PMD/SPG-2, which do not arise from P/p gene mutations. Furthermore, it is important to understand how the gone is regulated, in order to help promote the remyelination process in people with demyelinating diseases. Multiple sclerosis, the most common demyelinating disease, generally occurs in adults substantially after the active myelination period in CNS development has ended. A deletion-transfection analysis has confirmed the importance of regulatory sequences located within the first intron that are essential for regulating P/p gone expression. One of these elements, the so-called ASE, for antisilencer/enhancer, appears to cause a dramatic increase in P/p gene expression during (and after) the myelination period of CNS development. We believe that multiple factors assemble on the ASE to form a stereospecific nucleoprotein structure termed an "enhanceosome." To understand how the ASE mediates P/p gone activation, the following specific aims have been proposed: 1) Characterize further the ASE, a positive cis-acting regulatory element located in intron 1 DNA, which promotes high levels of P/p gene expression in oligodendrocytes; 2) Identify the nuclear factors, which form a transcriptional regulatory complex on the ASE; 3) Elucidate the mechanism whereby the ASE nucleoprotein complex activates P/p gone expression in oligodendrocytes.