Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions

作     者：Seiji Kaji Takakuni Maki Tomoyuki Ishimoto Hodaka Yamakado Ryosuke Takahashi 

作者机构：Department of NeurologyGraduate School of MedicineKyoto University54 Shogoin-Kawahara-choSakyo-kuKyotoJapan 

出 版 物：《Translational Neurodegeneration》 (转化神经变性病（英文）)

年 卷 期：2020年第9卷第1期

页      面：66-80页

核心收录：

学科分类：0710[理学-生物学] 0402[教育学-心理学(可授教育学、理学学位）] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 1010[医学-医学技术（可授医学、理学学位）] 100204[医学-神经病学] 10[医学] 1009[医学-特种医学] 

基　　金：This work was funded by the Japan Agency for Medical Research and Development(AMED,18ek0109384h0001,I9ek0109384h0002,T.M.,H.Y.,R.T.) Kyoto University MSA Research Fund(RT).S.K.is supported by Grant-in-Aid for Research Activity start-up(18H06088) Grant-in-Aid for Young Scientists(B)(19 K16915)from Japan Society for the Promotion of Science in Japan. 

主　　题：Multiple system atrophy a-synuclein Glial cytoplasmic inclusion Prion Neurodegeneration Oligodendrocyte Microglia Astrocyte Oligodendrocyte precursor cell 

摘      要：Multiple system atrophy(MSA)is a debilitating and fatal neurodegenerative disorder.The disease severity warrants urgent development of disease-modifying therapy,but the disease pathogenesis is still enigmatic.Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions(GCIs),which are insoluble α-synuclein accumulations within oligodendrocytes(OLGs).Thus,preventive strategies against GCI formation may suppress disease progression.However,although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation,difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs;asynuclein and OLGs.The difficulty originates from several enigmas:1)what triggers the initial generation and possible propagation of pathogenic α-synuclein species?2)what contributes to OLG-specific accumulation of α-synuclein,which is abundantly expressed in neurons but not in OLGs?and 3)how are OLGs and other glial cells affected and contribute to neurodegeneration?The primary pathogenesis of GCIs may involve myelin dysfunaion and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism.We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary α-synuclein.This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological α-synuclein into oligodendrocyte precursor cells.In this review,in order to discuss the pathogenesis of GCIs,we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies.Furthermore,we will introduce some hypotheses on how α-synuclein pathology spreads among OLGs in MSA brains,in the light of our data from the experiments with primary oligodendrocyte lineage cell culture.While various reports have focused on the mysterious source of α-synuclein in GCIs,insights into the mechanism which regulates the uptake of pathological α-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA.The interaction between glial cells and asynuclein is also highlighted with previous studies of post-mortem human brains,cultured cells,and animal models,which provide comprehensive insight into GCIs and the MSA pathomechanisms.