Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease.
Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease.
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在帕金森病的播种/扩散小鼠模型中，神经变性和神经炎症是相关的，但独立于α-突触核蛋白包涵体。
作者：
帕金森病 (PD) 的一个关键病理过程是 α-突触核蛋白的跨神经元扩散。 α-突触核蛋白 (α-syn) 是一种突触前蛋白，在 PD 中形成病理包涵体。 PD 的其他特征包括易感大脑区域的神经变性和小胶质细胞增生。目前尚不清楚是否主要是 α-syn 颗粒的跨神经元扩散、包涵体形成或其他机制（例如炎症）导致 PD 神经变性。我们使用将 α-syn 预制原纤维注射到小鼠纹状体中诱导 α-syn 扩散的模型来解决这个问题。我们对不同大脑区域的 α-syn 内含物、神经变性和小胶质细胞增生进行了定量分析，并在疾病诱导后的两个不同时间点生成了腹侧中脑的基因表达谱。我们在大脑区域观察到显着的神经变性和小胶质细胞增生，不仅有α-syn 内含物，而且没有α-syn 内含物。我们还在受伤的大脑区域观察到明显的小胶质细胞增生，这与神经变性或包涵体负荷无关。使用纵向基因表达谱，我们观察到与神经炎症相关的早期基因表达变化，这些变化发生在神经变性之前，表明小胶质细胞在此过程中发挥着积极作用。改变的基因途径与帕金森病的典型基因途径重叠。我们的观察表明，α-syn 包涵体的形成并不是 PD 样神经变性早期阶段的主要驱动因素，但由可扩散的寡聚 α-syn 激活的小胶质细胞可能在此过程中发挥关键作用。我们的研究结果揭示了 α-syn 诱导的病理学的新特征，特别是小胶质细胞增生，并指出有必要对 α-syn 传播过程有更广泛的了解。向小鼠纹状体注射突触核蛋白原纤维以建立帕金森病模型。内含物、神经变性、小胶质细胞增生之间没有相关性。转录组学揭示了神经退行性变之前的小胶质细胞反应。分子途径与 PD 的分子途径重叠。
A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α‐synuclein. Alpha‐synuclein (α‐syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α‐syn particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used a model of spreading of α‐syn induced by striatal injection of α‐syn preformed fibrils into the mouse striatum to address this question. We performed quantitative analysis for α‐syn inclusions, neurodegeneration, and microgliosis in different brain regions, and generated gene expression profiles of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α‐syn inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. Using longitudinal gene expression profiling, we observed early gene expression changes, linked to neuroinflammation, that preceded neurodegeneration, indicating an active role of microglia in this process. Altered gene pathways overlapped with those typical of PD. Our observations indicate that α‐syn inclusion formation is not the major driver in the early phases of PD‐like neurodegeneration, but that microglia, activated by diffusible, oligomeric α‐syn, may play a key role in this process. Our findings uncover new features of α‐syn induced pathologies, in particular microgliosis, and point to the necessity for a broader view of the process of α‐syn spreading. Striatal injection of synuclein fibrils in mice to model PD. No correlation between inclusions, neurodegeneration, microgliosis. Transcriptomics reveals microglia response preceding neurodegeneration. Molecular pathways overlap with those of PD.
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影响因子：
12.7
作者：
Bengoa-Vergniory N;Roberts RF;Wade-Martins R;Alegre-Abarrategui J
通讯作者：
Alegre-Abarrategui J
影响因子：
14.5
作者：
Chu, Yaping;Muller, Scott;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.
影响因子：
4.8
作者：
Brundin P;Ma J;Kordower JH
通讯作者：
Kordower JH
影响因子：
15.9
作者：
Brochard, Vanessa;Combadiere, Behazine;Hunot, Stephane
通讯作者：
Hunot, Stephane
影响因子：
48
作者：
Browaeys, Robin;Saelens, Wouter;Saeys, Yvan
通讯作者：
Saeys, Yvan