Department of Experimental Neurodegeneration, Centre for Biostructural Imaging of Neurodegeneration, University Medical Centre Göttingen, Göttingen, Germany.
Present address: Laboratory of Cognitive and Adaptive Neuroscience, UMR 7364 (CNRS/ Strasbourg University), Strasbourg, France.
J Parkinsons Dis. 2023;13(2):179-196. doi: 10.3233/JPD-225055.
Synucleinopathies are disorders characterized by the abnormal accumulation of α-synuclein (aSyn). Synaptic compromise is observed in synucleinopathies parallel to aSyn aggregation and is accompanied by transcript deregulation.
We sought to identify microRNAs associated with synaptic processes that may contribute to synaptic dysfunction and degeneration in synucleinopathies.
We performed small RNA-sequencing of midbrain from 6-month-old transgenic mice expressing A30P mutant aSyn, followed by comparative expression analysis. We then used real-time quantitative polymerase chain reaction (qPCR) for validation. Functional analysis was performed in primary neurons by biochemical assays and imaging.
We found several deregulated biological processes linked to the synapse. miR-101a-3p was validated as a synaptic miRNA upregulated in aSyn Tg mice and in the cortex of dementia with Lewy bodies patients. Mice and primary cultured neurons overexpressing miR-101a-3p showed downregulation of postsynaptic proteins GABA Ab2 and SAPAP3 and altered dendritic morphology resembling synaptic plasticity impairments and/or synaptic damage. Interestingly, primary cultured neuron exposure to recombinant wild-type aSyn species efficiently increased miR-101a-3p levels. Finally, a dynamic role of miR-101a-3p in synapse plasticity was shown by identifying downregulation of miR-101a-3p in a condition of enhanced synaptic plasticity modelled in Wt animals housed in enriched environment.
To conclude, we correlated pathologic aSyn with high levels of miR-101a-3p and a novel dynamic role of the miRNA in synaptic plasticity.
突触核蛋白病是一种以α-突触核蛋白（aSyn）异常积累为特征的疾病。在突触核蛋白病中，突触功能障碍与 aSyn 聚集平行发生，并伴有转录失调。
我们试图确定与突触过程相关的 microRNA，这些 microRNA 可能导致突触核蛋白病中的突触功能障碍和退化。
我们对表达 A30P 突变 aSyn 的 6 月龄转基因小鼠的中脑进行了小 RNA-seq 测序，然后进行了比较表达分析。接着我们使用实时定量聚合酶链反应（qPCR）进行了验证。在原代神经元中通过生化测定和成像进行了功能分析。
我们发现了几个与突触相关的失调生物学过程。miR-101a-3p 被验证为在 aSyn Tg 小鼠和路易体痴呆患者皮质中上调的突触 microRNA。过表达 miR-101a-3p 的小鼠和原代培养神经元表现出 postsynaptic 蛋白 GABA Ab2 和 SAPAP3 的下调以及树突形态改变，类似于突触可塑性损伤和/或突触损伤。有趣的是，原代培养神经元暴露于重组野生型 aSyn 物种会有效增加 miR-101a-3p 的水平。最后，通过在富含环境中饲养的 Wt 动物中增强突触可塑性的模型中鉴定 miR-101a-3p 的下调，表明 miR-101a-3p 在突触可塑性中的动态作用。
总之，我们将病理性 aSyn 与高水平的 miR-101a-3p 相关联，并发现了该 microRNA 在突触可塑性中的新的动态作用。
