Nuclear factor‐kappa B (NF‐κB) in pathophysiology of Parkinson disease: Diverse patterns and mechanisms contributing to neurodegeneration

Parkinson's disease (PD), the most common movement disorder, comprises several pathophysiologic mechanisms including misfolded alpha-synuclein aggregation, inflammation, mitochondrial dysfunction, and synaptic loss. Nuclear Factor-Kappa B (NF-κB), as a key regulator of a myriad of cellular reactions, is shown to be involved in such mechanisms associated with PD, and the changes in NF-κB expression is implicated in PD. Alpha-synuclein accumulation, the characteristic feature of PD pathology, is known to trigger NF-κB activation in neurons, thereby propagating apoptosis through several mechanisms. Furthermore, misfolded alpha-synuclein released from degenerated neurons, activates several signaling pathways in glial cells which culminate in activation of NF-κB and production of pro-inflammatory cytokines, thereby aggravating neurodegenerative processes. On the other hand, NF-κB activation, acting as a double-edged sword, can be necessary for survival of neurons. For instance, NF-κB activation is necessary for competent mitochondrial function and deficiency in c-Rel, one of the NF-κB proteins, is known to propagate DA neuron loss via several mechanisms. Despite the dual role of NF-κB in PD, several agents by selectively modifying the mechanisms and pathways associated with NF-κB, can be effective in attenuating DA neuron loss and PD, as reviewed in this paper.