Nuclear pore and nucleocytoplasmic transport impairment in oxidative stress-induced neurodegeneration: relevance to molecular mechanisms in Pathogenesis of Parkinson's and other related neurodegenerative diseases

Abstract

Nuclear pore complexes (NPCs) are embedded in the nuclear envelope and facilitate the exchange of macromolecules between the nucleus and cytoplasm in eukaryotic cells. The dysfunction of the NPC and nuclear transport plays a significant role in aging and the pathogenesis of various neurodegenerative diseases. Common features among these neurodegenerative diseases, including Parkinson's disease (PD), encompass mitochondrial dysfunction, oxidative stress and the accumulation of insoluble protein aggregates in specific brain regions. The susceptibility of dopaminergic neurons to mitochondrial stress underscores the pivotal role of mitochondria in PD progression. Disruptions in mitochondrial-nuclear communication are exacerbated by aging and α-synuclein-induced oxidative stress in PD. The precise mechanisms underlying mitochondrial impairment-induced neurodegeneration in PD are still unclear. Evidence suggests that perturbations in dopaminergic neuronal nuclei are linked to PD-related neurodegeneration. These perturbations involve structural damage to the nuclear envelope and mislocalization of pivotal transcription factors, potentially driven by oxidative stress or α-synuclein pathology. The presence of protein aggregates, pathogenic mutations, and ongoing oxidative stress can exacerbate the dysfunction of NPCs, yet this mechanism remains understudied in the context of oxidative stress-induced PD. This review summarizes the link between mitochondrial dysfunction and dopaminergic neurodegeneration and outlines the current evidence for nuclear envelope and nuclear transport abnormalities in PD, particularly in oxidative stress. We highlight the potential role of nuclear pore and nucleocytoplasmic transport dysfunction in PD and stress the importance of systematically investigating NPC components in PD.

Keywords: Alpha-synuclein; Neurodegeneration; Nuclear pore complex; Nucleocytoplasmic transport; Oxidative stress; Parkinson’s disease.

Fig. 1

Illustrations of the nuclear pore complex and classical nucleocytoplasmic transport. A Structure of the nuclear pore complex showing the main subcomplexes and their component nucleoporins (Nups). Created with BioRender.com. B In classical nuclear import, protein cargo containing the nuclear localization signal (NLS) is transported into the nucleus by importins. In classical nuclear export, protein cargo containing the nuclear export signal (NES) is exported from the nucleus by the exportin Crm1. The directionality of nucleocytoplasmic transport is mediated by Ran GTPase. After each nuclear export cycle, Ran-GDP is shuttled back to the nucleus by nuclear transport factor 2 (Ntf2). Adapted from “TRPS1 Transport into the Nucleus” , created by “Joshua Patrick” using BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates.

Fig. 2

The risk factors and molecular pathways associated with PD. A A schematic overview of the etiology of PD. B The interplay between mitochondrial dysfunction, oxidative stress, α-synuclein toxicity, and aberrant mitochondria-nuclear signaling contributes to DAergic neuron loss in PD. Created with BioRender.com

Fig. 3

Summary of mislocalization of specific proteins in DAergic neurons in PD. (1) Oxidative stressors increase the translocation of α-synuclein to the nucleus where it can markedly alter gene expression. This could account for the accumulation of phosphorylated α-synuclein in the nuclei of patient brains. (2) Phosphorylated extracellular signal-regulated kinase (ERK) and (3) total and phosphorylated cyclic AMP response element-binding protein (CREB) accumulate in the cytoplasm of dopaminergic neurons exposed to 6-hydroxydopamine and in PD patient neurons. A fraction of the cytoplasmic phospho-ERK also localizes to the mitochondria. Created with BioRender.com