Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation
Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation
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DOI：
10.1007/s00401-019-01961-w
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发表时间：
2019-03-01
影响因子：
12.7
通讯作者：
Toda, Tatsushi
中科院分区：
文献类型：
--
作者：
Sekiya, Hiroaki;Kowa, Hisatomo;Toda, Tatsushi
多系统萎缩症（MSA）是一种以不同程度的小脑功能障碍和帕金森综合征为特征的致死性成人神经退行性疾病。MSA的神经病理学标志是α-突触核蛋白（AS）阳性胶质细胞胞质包涵体（GCI）。虽然在MSA中也观察到严重的神经元损失（NL），但与GCI相比，神经元包涵体（NI）是罕见的，使得MSA中NL的病理机制尚不清楚。GCI和NI是相对于AS寡聚体的晚期病理学特征，可能不代表MSA的早期病理学变化。为了揭示MSA的早期病理学，有必要检查AS的早期聚集，即，AS低聚物。在这里，我们采用邻位连接分析（PLA），以检查AS寡聚体在脑组织样本中的分布与MSA和其他疾病的患者。令人惊讶的是，MSA大脑显示出广泛的分布和丰富的积累寡聚AS神经元以及少突胶质细胞的新皮层。在几个地区，低聚AS信号强度较高的情况下，MSA比帕金森病的情况下。与以前的研究相反，AS-PLA显示MSA脑中浦肯野细胞中有丰富的AS寡聚体积累，将寡聚体AS积累确定为浦肯野细胞损失的可能原因。AS寡聚体在MSA脑神经元中的这种广泛分布以前没有描述过，表明MSA中NL的病理机制。
Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. GCIs and NIs are late-stage pathology features relative to AS oligomers and may not represent early pathological changes in MSA. To reveal the early pathology of MSA, it is necessary to examine the early aggregation of AS, i.e., AS oligomers. Here, we adopted a proximity ligation assay (PLA) to examine the distribution of AS oligomers in brain tissue samples from patients with MSA and other diseases. Surprisingly, MSA brains showed a widespread distribution and abundant accumulation of oligomeric AS in neurons as well as oligodendrocytes of the neocortex. In several regions, oligomeric AS signal intensity was higher in cases with MSA than in cases with Parkinson's disease. In contrast to previous studies, AS-PLA revealed abundant AS oligomer accumulation in Purkinje cells in MSA brains, identifying oligomeric AS accumulation as a possible cause of Purkinje cell loss. This wide distribution of AS oligomers in MSA brain neurons has not been described previously and indicates a pathological mechanism of NL in MSA.