Santos Patrícia I, García-Plaza Inés Hojas, Shaib Ali, Rhee Jeong Seop, Chouaib Abed Alrahman, Brose Nils, Rizzoli Silvio O, Daniel James, Outeiro Tiago F
Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
NPJ Parkinsons Dis. 2025 Aug 12;11(1):238. doi: 10.1038/s41531-025-01085-x.
Alpha synuclein (aSyn) is abundant in the brain and strongly implicated in Parkinson's disease (PD), genetically and through its accumulation in neuronal pathognomonic inclusions. While mutations or increased expression of wild-type aSyn can cause familial PD, it remains unclear whether increased aSyn alone impairs presynaptic function. Here, we overexpressed human aSyn (haSyn) in rodent glutamatergic neurons and analysed presynaptic function. Expression levels mimicked SNCA gene triplications, as seen in certain familial forms of PD. In continental cultures, haSyn overexpression was not toxic nor did it alter the levels of presynaptic SNAP-25 or postsynaptic PSD-95. Analyses of autaptic neurons revealed no significant differences in evoked or spontaneous neurotransmission release, nor in synaptic plasticity. These results indicate that rodent glutamatergic neurons are resilient to aSyn overexpression. Our findings suggest neurotoxicity associated with aSyn overexpression is not universal, and that a deeper understanding of aSyn biology and pathobiology is necessary.
α-突触核蛋白（aSyn）在大脑中含量丰富，在帕金森病（PD）的发生中起着重要作用，这在遗传学上以及通过其在神经元特征性包涵体中的积累得到了证实。虽然野生型aSyn的突变或表达增加可导致家族性PD，但单独增加aSyn是否会损害突触前功能仍不清楚。在这里，我们在啮齿动物谷氨酸能神经元中过表达人aSyn（haSyn）并分析突触前功能。表达水平模拟了某些家族性PD形式中所见的SNCA基因三倍体。在大陆文化中，haSyn过表达无毒，也不会改变突触前SNAP-25或突触后PSD-95的水平。对自突触神经元的分析表明，诱发或自发神经递质释放以及突触可塑性均无显著差异。这些结果表明，啮齿动物谷氨酸能神经元对aSyn过表达具有耐受性。我们的研究结果表明，与aSyn过表达相关的神经毒性并不普遍，有必要更深入地了解aSyn生物学和病理生物学。
