α-突触核蛋白扩散对黑质纹状体多巴胺能通路的影响取决于病理的发生,Brain Pathology

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α-突触核蛋白扩散对黑质纹状体多巴胺能通路的影响取决于病理的发生
Brain Pathology ( IF 5.8 ) Pub Date : 2021-11-21 , DOI: 10.1111/bpa.13036
Fanfan Sun _{1,

2} , Armando G Salinas ₃ , Severin Filser _{4,

5} , Sonja Blumenstock _{1,

2,

4,

6} , Jose Medina-Luque _{1,

2} , Jochen Herms _{1,

2,

4} , Carmelo Sgobio _{1,

2}

Affiliation

错误折叠的 α-突触核蛋白沿着大脑中解剖学上相连的区域扩散，促使帕金森病的黑质纹状体通路进行性神经变性。为了研究错误折叠的 α-突触核蛋白沿黑质纹状体通路的早期播种和传播的影响，我们研究了单次急性 α-突触核蛋白预制原纤维 (PFF) 接种到中脑所引起的病理生理效应。此外，为了模拟表征多巴胺 (DA) 神经元寿命的渐进脆弱性，我们使用了两组不同年龄的小鼠：2 个月大（年轻）和 5 个月大（成年）小鼠。注射 α-突触核蛋白 PFF 两个月后，我们发现成年小鼠的纹状体 DA 释放仅减少。与年轻神经元相比，成年 DA 神经元表现出沿着黑质纹状体通路的病理学扩散程度增加，伴随中脑中 α-突触核蛋白沉积量减少、神经传递受损、DA 末端组成僵化以及小胶质细胞反应性降低。值得注意的是，在 PFFs 接种的半球中，保留的 DA 释放和增加的小胶质细胞覆盖率与年轻 DA 神经元中大尺寸终末密度的减少并存。这表明存在有针对性的修剪机制，限制了 α-突触核蛋白早期扩散的有害影响。这项研究表明，错误折叠的 α-突触核蛋白沿着黑质纹状体通路传播所引起的病理生理学影响取决于 DA 网络的年龄，特别是在成年小鼠中，减少了纹状体 DA 的释放。

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Impact of α-synuclein spreading on the nigrostriatal dopaminergic pathway depends on the onset of the pathology

Misfolded α-synuclein spreads along anatomically connected areas through the brain, prompting progressive neurodegeneration of the nigrostriatal pathway in Parkinson's disease. To investigate the impact of early stage seeding and spreading of misfolded α-synuclein along with the nigrostriatal pathway, we studied the pathophysiologic effect induced by a single acute α-synuclein preformed fibrils (PFFs) inoculation into the midbrain. Further, to model the progressive vulnerability that characterizes the dopamine (DA) neuron life span, we used two cohorts of mice with different ages: 2-month-old (young) and 5-month-old (adult) mice. Two months after α-synuclein PFFs injection, we found that striatal DA release decreased exclusively in adult mice. Adult DA neurons showed an increased level of pathology spreading along with the nigrostriatal pathway accompanied with a lower volume of α-synuclein deposition in the midbrain, impaired neurotransmission, rigid DA terminal composition, and less microglial reactivity compared with young neurons. Notably, preserved DA release and increased microglial coverage in the PFFs-seeded hemisphere coexist with decreased large-sized terminal density in young DA neurons. This suggests the presence of a targeted pruning mechanism that limits the detrimental effect of α-synuclein early spreading. This study suggests that the impact of the pathophysiology caused by misfolded α-synuclein spreading along the nigrostriatal pathway depends on the age of the DA network, reducing striatal DA release specifically in adult mice.

更新日期：2021-11-21

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