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

点击翻译按钮获取中文摘要

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.