Targeted modulation of NF-κB1 in neurodegenerative diseases

Abstract

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal dysfunction and loss driven by convergent pathological mechanisms such as oxidative stress, mitochondrial impairment, protein misfolding, apoptosis, and neuroinflammation. Among transcriptional regulators implicated in these processes, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway has emerged as a critical mediator of inflammatory and survival signaling. Notably, the NF-κB1 (p50) subunit exhibits context-dependent transcriptional activity, mediating both neuroprotective and neurotoxic outcomes depending on cellular identity and activation dynamics. Aberrant NF-κB1 signaling has been linked to chronic neuroinflammation and neuronal apoptosis; however, emerging evidence suggests that selective, context-specific modulation of NF-κB1 may confer neuroprotective effects. Interactions between mutant huntingtin protein and NF-κB signaling pathways further underscore the importance of transcriptional regulatory networks in Huntington’s disease progression. This review critically synthesizes current evidence on NF-κB1-dependent mechanisms in neurodegeneration, with emphasis on subunit-specific signaling, cellular context, and therapeutic feasibility. By examining molecular pathways linking NF-κB1 to neuronal survival, neuroinflammation, and synaptic regulation, we highlight unresolved mechanistic questions and identify translational opportunities for targeted gene modulation strategies.