NF-κB/c-Rel DNA-binding is reduced in substantia nigra and peripheral blood mononuclear cells of Parkinson's disease patients

• Published in: Neurobiology of disease 2023-05, Vol.180, p.106067-106067, Article 106067
• Main Authors: Porrini, Vanessa, Pilotto, Andrea, Vezzoli, Marika, Lanzillotta, Annamaria, Gennari, Michele M., Bonacina, Sonia, Alberici, Antonella, Turrone, Rosanna, Bellucci, Arianna, Antonini, Angelo, Padovani, Alessandro, Pizzi, Marina
• Format: Article
• Language: English
• Subjects: Animals; c-Rel; Dopaminergic Neurons - metabolism; Humans; Leukocytes, Mononuclear - metabolism; Mice; MPTP Poisoning - pathology; NF-kappa B - metabolism; NF-κB; Parkinson Disease - metabolism; Parkinson's disease; Peripheral blood mononuclear cells; Proto-Oncogene Proteins c-rel - metabolism; Substantia Nigra - metabolism
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2023.106067

Although Parkinson's disease (PD) key neuropathological hallmarks are well known, the underlying pathogenic mechanisms of the disease still need to be elucidated to identify innovative disease-modifying drugs and specific biomarkers. NF-κB transcription factors are involved in regulating several processes associated with neurodegeneration, such as neuroinflammation and cell death, that could be related to PD pathology. NF-κB/c-Rel deficient (c-rel−/−) mice develop a progressive PD-like phenotype. The c-rel−/− mice present both prodromal and motor symptoms as well as key neuropathological features, including nigrostriatal dopaminergic neurons degeneration, accumulation of pro-apoptotic NF-κB/RelA acetylated at the lysine 310 residue (Ac-RelA(lys310)) and progressive caudo-rostral brain deposition of alpha-synuclein. c-Rel inhibition can exacerbate MPTP-induced neurotoxicity in mice. These findings support the claim that misregulation of c-Rel protein may be implicated in PD pathophysiology. In this study, we aimed at evaluating c-Rel levels and DNA-binding activity in human brains and peripheral blood mononuclear cells (PBMCs) of sporadic PD patients. We analyzed c-Rel protein content and activity in frozen substantia nigra (SN) samples from post-mortem brains of 10 PD patients and 9 age-matched controls as well as in PBMCs from 72 PD patients and 40 age-matched controls. c-Rel DNA-binding was significantly lower and inversely correlated with Ac-RelA(lys310) content in post-mortem SN of sporadic PD cases, when compared to healthy controls. c-Rel DNA-binding activity was also reduced in PBMCs of followed-up PD subjects. The decrease of c-Rel activity in PBMCs from PD patients appeared to be independent from dopaminergic medication or disease progression, as it was evident even in early stage, drug-naïve patients. Remarkably, the levels of c-Rel protein were comparable in PD and control subjects, pointing out a putative role for post-translational modifications of the protein in c-Rel dysfunctions. These findings support that PD is characterized by the loss of NF-κB/c-Rel activity that potentially has a role in PD pathophysiology. Future studies will be aimed at addressing whether the reduction of c-Rel DNA-binding could constitute a novel biomarker for PD. •c-Rel DNA-binding activity is reduced in substantia nigra and PBMCs of PD patients.•c-Rel protein levels were comparable in PD and control subjects' specimens.•Deficit of c-Rel activity is evident in PBMC