Martínez-Rojas Vladimir A, Pischedda Francesca, Romero-Maldonado Isabel, Khalaf Bouchra, Piccoli Giovanni, Macchi Paolo, Musio Carlo
Institute of Biophysics-IBF, National Research Council-CNR, Via Sommarive 18, 38123 Trento, Italy.
Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy.
Life (Basel). 2023 Aug 22;13(9):1791. doi: 10.3390/life13091791.
Nucleoporins (NUPs) are proteins that comprise the nuclear pore complexes (NPCs). The NPC spans the nuclear envelope of a cell and provides a channel through which RNA and proteins move between the nucleus and the cytoplasm and vice versa. NUP and NPC disruptions have a great impact on the pathophysiology of neurodegenerative diseases (NDDs). Although the downregulation of Nup358 leads to a reduction in the scaffold protein ankyrin-G at the axon initial segment (AIS) of mature neurons, the function of Nup358 in the cytoplasm of neurons remains elusive. To investigate whether Nup358 plays any role in neuronal activity, we downregulated Nup358 in non-pathological mouse cortical neurons and measured their active and passive bioelectrical properties. We identified that Nup358 downregulation is able to produce significant modifications of cell-membrane excitability via voltage-gated sodium channel kinetics. Our findings suggest that Nup358 contributes to neuronal excitability through a functional stabilization of the electrical properties of the neuronal membrane. Hypotheses will be discussed regarding the alteration of this active regulation as putatively occurring in the pathophysiology of NDDs.
核孔蛋白（NUPs）是构成核孔复合体（NPCs）的蛋白质。核孔复合体横跨细胞的核膜，提供了一个通道，RNA和蛋白质可通过该通道在细胞核与细胞质之间相互移动。核孔蛋白和核孔复合体的破坏对神经退行性疾病（NDDs）的病理生理学有重大影响。尽管Nup358的下调会导致成熟神经元轴突起始段（AIS）的支架蛋白锚蛋白G减少，但Nup358在神经元细胞质中的功能仍不清楚。为了研究Nup358是否在神经元活动中发挥任何作用，我们在非病理性小鼠皮层神经元中下调了Nup358，并测量了它们的主动和被动生物电特性。我们发现，Nup358的下调能够通过电压门控钠通道动力学对细胞膜兴奋性产生显著改变。我们的研究结果表明，Nup358通过对神经元膜电特性的功能稳定作用来促进神经元兴奋性。将讨论关于这种主动调节的改变在NDDs病理生理学中可能发生的假设。
