Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe, 654-0142, Japan.
Acta Neuropathol. 2019 Mar;137(3):455-466. doi: 10.1007/s00401-019-01961-w. Epub 2019 Feb 5.
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.
多系统萎缩（MSA）是一种致命的成人发病的神经退行性疾病，其特征是小脑功能障碍和帕金森病的程度不同。MSA 的神经病理学标志是α-突触核蛋白（AS）阳性神经胶质细胞质包含物（GCIs）。尽管 MSA 中也观察到严重的神经元丢失（NL），但与 GCIs 相比，神经元包含物（NIs）很少，因此 MSA 中 NL 的病理机制尚不清楚。GCIs 和 NIs 是相对于 AS 低聚物的晚期病理学特征，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，我们采用邻近连接测定（PLA）来检查 MSA 患者和其他疾病患者脑组织样本中 AS 低聚物的分布。令人惊讶的是，MSA 大脑显示出神经元和新皮层的少突胶质细胞中广泛分布和大量聚集的寡聚 AS。在几个区域，AS-PLA 显示 MSA 病例中的寡聚 AS 信号强度高于帕金森病病例。与之前的研究不同，AS-PLA 鉴定出 MSA 大脑中浦肯野细胞中存在大量 AS 寡聚物的积累，这表明寡聚 AS 积累可能是浦肯野细胞丢失的原因之一。AS 寡聚物在 MSA 大脑神经元中的广泛分布以前没有被描述过，这表明了 MSA 中 NL 的病理机制。
