The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding
The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding
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DOI：
10.1038/s41598-020-61757-x
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发表时间：
2020-03-17
影响因子：
4.6
通讯作者：
Peyrin, Jean-Michel
中科院分区：
文献类型：
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作者：
Courte, Josquin;Bousset, Luc;Peyrin, Jean-Michel
富含α-突触核蛋白（aSyn）的聚集体在神经元网络中传播并损害细胞稳态，导致突触核蛋白病如帕金森病。聚合aSyn扩散遵循保守的时空模式，其不仅仅依赖于连接性。因此，富含aSyn的聚集体对不同脑区域的差异向性，或它们在这些区域内扩增的能力，必须有助于这一过程。为了更好地理解脑内富含aSyn的聚集体分布的基础，我们从野生型小鼠和表达降低水平的aSyn的小鼠的各种脑区域产生原代神经元培养物，并将它们暴露于纤维状aSyn。然后，我们评估了外源性纤维状aSyn摄取、内源性aSyn接种和内源性aSyn生理表达水平。尽管来自不同脑区域的神经元细胞对外源性原纤维的摄取相似，但内源性aSyn的接种聚集在一个神经元群体与另一个神经元群体之间差异很大。神经元群体的不同易感性与其aSyn表达水平有关。我们的数据证实内源性aSyn表达水平在纤维状aSyn朊病毒样播种中起关键作用，支持内源性aSyn表达水平参与选择性区域脑脆弱性。
Alpha-synuclein (aSyn)-rich aggregates propagate in neuronal networks and compromise cellular homeostasis leading to synucleinopathies such as Parkinson's disease. Aggregated aSyn spread follows a conserved spatio-temporal pattern that is not solely dependent on connectivity. Hence, the differential tropism of aSyn-rich aggregates to distinct brain regions, or their ability to amplify within those regions, must contribute to this process. To better understand what underlies aSyn-rich aggregates distribution within the brain, we generated primary neuronal cultures from various brain regions of wild-type mice and mice expressing a reduced level of aSyn, and exposed them to fibrillar aSyn. We then assessed exogenous fibrillar aSyn uptake, endogenous aSyn seeding, and endogenous aSyn physiological expression levels. Despite a similar uptake of exogenous fibrils by neuronal cells from distinct brain regions, the seeded aggregation of endogenous aSyn differed greatly from one neuronal population to another. The different susceptibility of neuronal populations was linked to their aSyn expression level. Our data establish that endogenous aSyn expression level plays a key role in fibrillar aSyn prion-like seeding, supporting that endogenous aSyn expression level participates in selective regional brain vulnerability.