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Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis
Cell Death & Disease ( IF 9 ) Pub Date : 2021-01-13 , DOI: 10.1038/s41419-020-03369-x
Jian-Jun Guo 1 , Feng Yue 2 , Dong-Yan Song 1 , Luc Bousset 3 , Xin Liang 4 , Jing Tang 4 , Lin Yuan 5 , Wen Li 5, 6 , Ronald Melki 3 , Yong Tang 4 , Piu Chan 2 , Chuang Guo 1 , Jia-Yi Li 1, 5, 6
Affiliation  

Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.



中文翻译:

鼻内给予α-突触核蛋白预制原纤维触发束状猕猴黑质中的小胶质细胞铁沉积

帕金森病(PD)患者脑部主要病变区域存在铁沉积,铁含量异常可能与多巴胺能神经元细胞毒性和中脑黑质变性有关。然而,铁沉积的原因及其在PD病理过程中的作用尚不清楚。在本研究中,我们研究了合成人 α-突触核蛋白 (α-syn) 预制原纤维 (PFF) 鼻粘膜递送对食蟹猴PD 发病机制的影响。我们检测到,黑质和苍白球中的铁沉积在 1 至 17 个月内以时间依赖性方式明显增加,与 α-syn PFF 治疗后的其他大脑区域形成鲜明对比。在细胞水平上,铁沉积物特异性地集中在小胶质细胞中,但不在多巴胺能神经元中,也不在黑质中的其他类型的神经胶质细胞中,而转铁蛋白(TF)、TF受体1(TFR1)、TF受体2的表达(TFR2) 和铁转运蛋白 (FPn) 在多巴胺能神经元中增加。此外,在黑质中没有观察到明显的多巴胺能神经元损失,但酪氨酸羟化酶(TH)的免疫反应性降低,壳核中出现轴突肿胀。大脑区域富集和细胞类型依赖性铁定位表明,鼻内 α-syn PFF 治疗诱导的黑质小胶质细胞中的铁沉积可能表现为一种早期细胞反应,可能在细胞死亡前引发多巴胺能系统中的神经炎症发生。我们的数据表明,抑制铁沉积可能是帕金森病早期预防和治疗的潜在方法。

更新日期:2021-01-13
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