alpha-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy

作者：May Verena E L; Ettle Benjamin; Poehler Anne Maria; Nuber Silke; Ubhi Kiren; Rockenstein Edward; Winner Beate; Wegner Michael; Masliah Eliezer; Winkler Juergen^*

来源：Neurobiology of Aging, 2014, 35(10): 2357-2368.

DOI：10.1016/j.neurobiolaging.2014.02.028

• Oligodendrocyte precursors
• Multiple system atrophy
• Platelet derived growth factor receptor alpha
• Alpha-synuclein
• Oligodendrogenesis
• Myelin basic protein
• Transgenic
• CG4
• Differentiation maturation

Multiple system atrophy (MSA), an atypical parkinsonian disorder, is characterized by alpha-synuclein (alpha-syn(+)) cytoplasmatic inclusions in mature oligodendrocytes. Oligodendrocyte progenitor cells (OPCs) represent a distinct cell population with the potential to replace dysfunctional oligodendrocytes. However, the role of OPCs in MSA and their potential to replace mature oligodendrocytes is still unclear. A postmortem analysis in MSA patients revealed alpha-syn within OPCs and an increased number of striatal OPCs. In an MSA mouse model, an age-dependent increase of dividing OPCs within the striatum and the cortex was detected. Despite of myelin loss, there was no reduction of mature oligodendrocytes in the corpus callosum or the striatum. Dissecting the underlying molecular mechanisms an oligodendroglial cell line expressing human alpha-syn revealed that alpha-syn delays OPC maturation by severely downregulating myelin-gene regulatory factor and myelin basic protein. Brain-derived neurotrophic factor was reduced in MSA models and its in vitro supplementation partially restored the phenotype. Taken together, efficacious induction of OPC maturation may open the window to restore glial and neuronal function in MSA.

• 出版日期2014-10