Postmortem Evaluation of Topoisomerase IIβ, Nurr1, and Neuroinflammatory Signatures in Parkinson's Disease

The selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta is a major mystery in the pathogenesis of Parkinson's disease (PD). A growing body of evidence points to the fact that the neurodegenerative process is a result of a complicated interaction between transcriptional dysregulation and chronic neuroinflammation. This study specifically investigates three key molecular regulators; DNA topoisomerase IIβ (topo IIβ), Nuclear Receptor Related 1 (Nurr1) and Nuclear Factor kappa B (NF-κB). The hypothesis posits that the interplay between these factors forms a critical transcriptional-inflammatory axis, and its disruption may significantly contribute to the progression of PD. Using immunohistochemical and western blot analyses on postmortem substantia nigra tissue samples from patients with PD and neurologically healthy controls, the study revealed a pronounced decrease in the expression levels of topo IIβ and Nurr1 in the PD samples. This decline indicates a substantial deterioration in transcriptional integrity and a departure from the cellular identity of dopaminergic neurons. Concurrentl, the analysis showed a substantial reduction in the unphosphorylated basal forms of the NF-κB p65 subunit, suggesting the potential loss of homeostatic inflammatory signaling, or the loss of the neurons' responsiveness entirely. The finding support a model wherein the failure of primary transcriptional maintenance, indicated by decreased levels of topo IIβ and Nurr1, is the critical for the loss of dopaminergic neuron phenotype and intrinsic mechanisms that uphoald and an anti-inflammatory state within these cells. The deficiency in inflammatory signaling appears to diminish the neurons’ resilience against degenerative processes, thereby accelerating neurodegeneration. This research identifies the topo IIβ-Nurr1-NF-κB axis as a novel and upstream pathogenic hub, highlighting its potential as a strategic target for the development of future disease-modifying therapies for PD.