NF-κB/c-Rel DNA-binding is reduced in substantia nigra and peripheral blood mononuclear cells of Parkinson's disease patients
Copyright © 2023. Published by Elsevier Inc..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:180 |
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| Enthalten in: |
Neurobiology of disease - 180(2023) vom: 10. Mai, Seite 106067 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Porrini, Vanessa [VerfasserIn] |
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| Links: |
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| Themen: |
C-Rel |
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| Anmerkungen: |
Date Completed 18.04.2023 Date Revised 21.04.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.nbd.2023.106067 |
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| PPN (Katalog-ID): |
NLM353996033 |
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| 100 | 1 | |a Porrini, Vanessa |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a NF-κB/c-Rel DNA-binding is reduced in substantia nigra and peripheral blood mononuclear cells of Parkinson's disease patients |
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| 520 | |a Copyright © 2023. Published by Elsevier Inc. | ||
| 520 | |a 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 | ||
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a NF-κB | |
| 650 | 4 | |a Parkinson's disease | |
| 650 | 4 | |a Peripheral blood mononuclear cells | |
| 650 | 4 | |a c-Rel | |
| 650 | 7 | |a NF-kappa B |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-rel |2 NLM | |
| 700 | 1 | |a Pilotto, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Vezzoli, Marika |e verfasserin |4 aut | |
| 700 | 1 | |a Lanzillotta, Annamaria |e verfasserin |4 aut | |
| 700 | 1 | |a Gennari, Michele M |e verfasserin |4 aut | |
| 700 | 1 | |a Bonacina, Sonia |e verfasserin |4 aut | |
| 700 | 1 | |a Alberici, Antonella |e verfasserin |4 aut | |
| 700 | 1 | |a Turrone, Rosanna |e verfasserin |4 aut | |
| 700 | 1 | |a Bellucci, Arianna |e verfasserin |4 aut | |
| 700 | 1 | |a Antonini, Angelo |e verfasserin |4 aut | |
| 700 | 1 | |a Padovani, Alessandro |e verfasserin |4 aut | |
| 700 | 1 | |a Pizzi, Marina |e verfasserin |4 aut | |
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