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Abstract
Parkinson’s disease (PD) is a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction plays a key role in the etiology of idiopathic and genetic PD. The mitochondrial-nuclear communication is impaired in PD-related neurodegeneration and current evidence strongly implicates deterioration of neuronal nuclei in disease progression. In this dissertation, we demonstrate that the nuclear pore complex (NPC) and nucleocytoplasmic transport are disrupted in mitochondrial dysfunction models of PD. We have found significant reduction of nucleoporins (Nups) within dopaminergic neurons in both cell-based and mouse models of mitochondrial dysfunction. Moreover, we observed mislocalization and cytoplasmic accumulation of the central channel FG-Nup, Nup62, in these neurons. The gradient of the nucleocytoplasmic trafficking protein Ran is disrupted in these models, and classical nuclear export is impaired in dopaminergic neural cells with mitochondrial dysfunction. Importantly, Nup pathology and Ran gradient loss are observed in nigral dopaminergic neurons of human PD post-mortem tissue, highlighting the clinical relevance of nuclear pore dysfunction in PD pathogenesis. Next, we identify simultaneous hyperphosphorylation and O-GlcNAc reduction of Nups as a potential mechanism of mitochondrial stress-induced NPC dysfunction in dopaminergic neurons. Several Nups are differentially phosphorylated, with drastic hyperphosphorylation observed in Nup50 and Nup153. Simultaneously, O-GlcNAcylation of Nup153 and Nup214 is notably decreased. Our data shows that Nup153 is hyperphosphorylated and hypo-O-GlcNAcylated at adjacent sites within the N-terminal region, and its interaction with Nup50 is impaired under conditions of mitochondrial stress. Finally, we show that mitochondrial dysfunction induces Lamin B1 invaginations, accumulation of the inner nuclear membrane protein SUN1, and nuclear membrane defects in dopaminergic neurons. Collectively, the results outlined in this dissertation propose that abnormal activation of signaling pathways by mitochondrial stress contribute to deterioration of the nuclear envelope structure, dysregulation of NPCs, and impairment of nucleocytoplasmic transport in dopaminergic neurons. These findings provide deeper understanding of the precise mechanisms driving mitochondrial dysfunction-induced dopaminergic neurodegeneration, directly linking abnormalities in Nups to this pathological process.