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NF-κB in neurodegenerative diseases: Recent evidence from human genetics

The transcription factor NF-κB is commonly known to drive inflammation and cancer progression, but is also a crucial regulator of a broad range of cellular processes within the mammalian nervous system. In the present review, we provide an overview on the role of NF-κB in the nervous system particul...

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Autores principales: Kaltschmidt, Barbara, Helweg, Laureen P., Greiner, Johannes F. W., Kaltschmidt, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380593/
https://www.ncbi.nlm.nih.gov/pubmed/35983068
http://dx.doi.org/10.3389/fnmol.2022.954541
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author Kaltschmidt, Barbara
Helweg, Laureen P.
Greiner, Johannes F. W.
Kaltschmidt, Christian
author_facet Kaltschmidt, Barbara
Helweg, Laureen P.
Greiner, Johannes F. W.
Kaltschmidt, Christian
author_sort Kaltschmidt, Barbara
collection PubMed
description The transcription factor NF-κB is commonly known to drive inflammation and cancer progression, but is also a crucial regulator of a broad range of cellular processes within the mammalian nervous system. In the present review, we provide an overview on the role of NF-κB in the nervous system particularly including its constitutive activity within cortical and hippocampal regions, neuroprotection as well as learning and memory. Our discussion further emphasizes the increasing role of human genetics in neurodegenerative disorders, namely, germline mutations leading to defects in NF-κB-signaling. In particular, we propose that loss of function mutations upstream of NF-κB such as ADAM17, SHARPIN, HOIL, or OTULIN affect NF-κB-activity in Alzheimer’s disease (AD) patients, in turn driving anatomical defects such as shrinkage of entorhinal cortex and the limbic system in early AD. Similarly, E3 type ubiquitin ligase PARKIN is positively involved in NF-κB signaling. PARKIN loss of function mutations are most frequently observed in Parkinson’s disease patients. In contrast to AD, relying on germline mutations of week alleles and a disease development over decades, somatic mutations affecting NF-κB activation are commonly observed in cells derived from glioblastoma multiforme (GBM), the most common malignant primary brain tumor. Here, our present review particularly sheds light on the mutual exclusion of either the deletion of NFKBIA or amplification of epidermal growth factor receptor (EGFR) in GBM, both resulting in constitutive NF-κB-activity driving tumorigenesis. We also discuss emerging roles of long non-coding RNAs such as HOTAIR in suppressing phosphorylation of IκBα in the context of GBM. In summary, the recent progress in the genetic analysis of patients, particularly those suffering from AD, harbors the potential to open up new vistas for research and therapy based on TNFα/NF-κB pathway and neuroprotection.
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spelling pubmed-93805932022-08-17 NF-κB in neurodegenerative diseases: Recent evidence from human genetics Kaltschmidt, Barbara Helweg, Laureen P. Greiner, Johannes F. W. Kaltschmidt, Christian Front Mol Neurosci Molecular Neuroscience The transcription factor NF-κB is commonly known to drive inflammation and cancer progression, but is also a crucial regulator of a broad range of cellular processes within the mammalian nervous system. In the present review, we provide an overview on the role of NF-κB in the nervous system particularly including its constitutive activity within cortical and hippocampal regions, neuroprotection as well as learning and memory. Our discussion further emphasizes the increasing role of human genetics in neurodegenerative disorders, namely, germline mutations leading to defects in NF-κB-signaling. In particular, we propose that loss of function mutations upstream of NF-κB such as ADAM17, SHARPIN, HOIL, or OTULIN affect NF-κB-activity in Alzheimer’s disease (AD) patients, in turn driving anatomical defects such as shrinkage of entorhinal cortex and the limbic system in early AD. Similarly, E3 type ubiquitin ligase PARKIN is positively involved in NF-κB signaling. PARKIN loss of function mutations are most frequently observed in Parkinson’s disease patients. In contrast to AD, relying on germline mutations of week alleles and a disease development over decades, somatic mutations affecting NF-κB activation are commonly observed in cells derived from glioblastoma multiforme (GBM), the most common malignant primary brain tumor. Here, our present review particularly sheds light on the mutual exclusion of either the deletion of NFKBIA or amplification of epidermal growth factor receptor (EGFR) in GBM, both resulting in constitutive NF-κB-activity driving tumorigenesis. We also discuss emerging roles of long non-coding RNAs such as HOTAIR in suppressing phosphorylation of IκBα in the context of GBM. In summary, the recent progress in the genetic analysis of patients, particularly those suffering from AD, harbors the potential to open up new vistas for research and therapy based on TNFα/NF-κB pathway and neuroprotection. Frontiers Media S.A. 2022-08-02 /pmc/articles/PMC9380593/ /pubmed/35983068 http://dx.doi.org/10.3389/fnmol.2022.954541 Text en Copyright © 2022 Kaltschmidt, Helweg, Greiner and Kaltschmidt. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Neuroscience
Kaltschmidt, Barbara
Helweg, Laureen P.
Greiner, Johannes F. W.
Kaltschmidt, Christian
NF-κB in neurodegenerative diseases: Recent evidence from human genetics
title NF-κB in neurodegenerative diseases: Recent evidence from human genetics
title_full NF-κB in neurodegenerative diseases: Recent evidence from human genetics
title_fullStr NF-κB in neurodegenerative diseases: Recent evidence from human genetics
title_full_unstemmed NF-κB in neurodegenerative diseases: Recent evidence from human genetics
title_short NF-κB in neurodegenerative diseases: Recent evidence from human genetics
title_sort nf-κb in neurodegenerative diseases: recent evidence from human genetics
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380593/
https://www.ncbi.nlm.nih.gov/pubmed/35983068
http://dx.doi.org/10.3389/fnmol.2022.954541
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