The role of oligodendroglial differentiation inhibitors p57kip2 and GPR17 in the pathology of Multiple Sclerosis

少突胶质细胞是中枢神经系统(CNS)中的髓鞘胶质细胞，通过产生髓鞘为CNS神经元的突起(即所谓的轴突)提供保护、稳定和电绝缘。在炎症性自身免疫性中枢神经系统疾病多发性硬化(MS)的病理生理条件下，这些结构会受到免疫系统的攻击，最终解体，导致严重的临床症状，如感觉异常、瘫痪或共济失调。少突胶质细胞的前体细胞分布于整个成人脑内，在髓鞘和神经纤维再生方面发挥着重要作用，从而对临床功能恢复起着重要作用。然而，成功修复中枢神经系统的先决条件是将这些细胞分化为成熟的髓鞘形成的少突胶质细胞，这一过程通常会被活跃的抑制髓鞘形成的分子所阻碍。在髓鞘少突胶质细胞糖蛋白实验性自身免疫性脑脊髓炎(MOG-EAE)的大鼠MS模型中，申请人可以确定p57Kip2基因是一种有效的髓鞘胶质细胞分化抑制因子，可以积极地阻止OPC分化。由于这一观察为未来的治疗方法提供了新的视角，以克服脱髓鞘疾病中出现的内源性再髓鞘抑制，重要的是揭示p57Kip2在MS患者脑组织中的存在程度以及它是否影响少突胶质细胞的分化和生存。此外，由于还有其他几个抑制因子，如最近描述的G蛋白偶联受体GPR17，它被发现通过与p57Kip2信号相似的细胞内过程干扰OPC的分化，申请人希望研究这两个因素在中枢神经系统炎症过程中相互作用的程度。阐明这两个分子在抑制MS的胶质细胞分化过程和修复活性方面是否可能在功能上汇聚或协同作用，以确定新的潜在治疗途径，有望提高临床治疗策略，这一点很重要。

Oligodendrocytes, the myelinating glial cells of the central nervous system (CNS) provide protection, stability and electrical insulation to the processes of CNS neurons, the so-called axons, by producing myelin sheaths. Under pathophysiological conditions as they occur in the inflammatory autoimmune CNS disease Multiple Sclerosis (MS) these structures are attacked by the immune system and ultimately disintegrate leading to severe clinical symptoms such as paraesthesia, paresis or ataxia. The progenitors of the oligodendrocytes, the oligodendroglial precursor cells (OPCs) which are dispersed throughout the entire adult brain, play an important role regarding myelin sheath and nerve fiber regeneration and thus for clinical functional recovery. However, the prerequisite for successful CNS repair is the differentiation of these cells into mature myelin-forming oligodendrocytes, a process which is often impeded by molecules that actively inhibit myelin formation. In myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis (MOG-EAE), the rat MS model, the applicant could identify the p57kip2 gene as a potent myelinating glial cell differentiation inhibitor which actively prevents OPC differentiation. As this observation provides new perspectives for future therapeutic approaches to overcome the endogenous remyelination blockade seen in demyelinating diseases it is important to reveal to what extent p57kip2 is also present in the brain tissue of MS patients and whether it affects oligodendroglial differentiation and survival. Furthermore, as there are several other inhibitory factors such as the recently described G protein-coupled receptor GPR17 which was found to interfere with OPC differentiation via intracellular processes similar to the ones observed in p57kip2 signaling the applicant would like to study to which extent these two factors interact during CNS inflammation. It is important to elucidate if these two molecules might converge functionally or act synergistically in the inhibition of glial differentiation processes and repair activity in MS in order to identify new potential therapeutic avenues which prospectively could result in enhanced clinical treatment strategies.