Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Abstract

The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

Velvet Antler Methanol Extracts Ameliorate Parkinson’s Disease by Inhibiting Oxidative Stress and Neuroinflammation: From C. elegans to Mice

“…Akt, NF- κ B, and p38 are dysregulated in the brain of PD patients [ 24 , 50 – 52 ] and are the main components in the signal transduction pathway predominantly responsible for the generation of ROS and proinflammatory factors [ 53 ]. To investigate how MEs affect ROS and neuroinflammation in MPTP-induced PD mice, the effect of MEs on the phosphorylation of Akt, NF- κ B, and p38 in the striatum was measured.…”

Genistein alleviates chronic vascular inflammatory response via the miR‑21/NF‑κB p65 axis in lipopolysaccharide‑treated mice

“…iNOS is only expressed under pathological conditions and catalyzes L-arginine to NO, and iNOS is closely associated with vascular inflammation ( 56 ). The NF-κB family is composed of p65, p50, p52, RelB and c-Rel, which combine to form transcriptionally active dimers ( 57 ). After activation, p65 is transported from the cytoplasm to the nucleus.…”

Loliolide, a New Therapeutic Option for Neurological Diseases? In Vitro Neuroprotective and Anti-Inflammatory Activities of a Monoterpenoid Lactone Isolated from Codium tomentosum

“…The nuclear factor NF- k B is a protein complex that regulates cytokines production, playing a crucial role in the regulation of inflammation and apoptosis involved in the brain programming of systemic aging, as well as in the pathogenesis of several neurodegenerative diseases, including PD [ 19 ]. In an oxidative condition, NF- k B initiates the transcription of proinflammatory genes coding cytokines and proteolytic enzymes.…”

“…However, NF- k B factor is composed by different dimers that can have either protective or noxious effects. For example, p50/RelA dimers induce pro-apoptotic and c-Rel-containing dimers exert neuroprotective actions [ 19 ]. Studies in another PD model also reported dopaminergic neuron loss in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mouse model suggesting that RelA upregulation may play a role in dopaminergic neuron degeneration when RelA is subexpressed [ 20 ].…”

“…Studies in another PD model also reported dopaminergic neuron loss in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mouse model suggesting that RelA upregulation may play a role in dopaminergic neuron degeneration when RelA is subexpressed [ 20 ]. On the other hand, studies in deficient mice for c-Rel subunit verified that this subunit can exert pro-survival effects, suggesting that a reduction in the protective function of c-Rel may render dopaminergic neurons more vulnerable to aging [ 19 ]. As a result, current research has been focused in finding substances that act to prevent mitochondrial dysfunction, oxidative stress, and inflammation for the development of more efficient therapies.…”