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

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

doi:10.1016/j.nbd.2023.106067

Cited by 3 publications

(3 citation statements)

References 74 publications

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“…REL promotes survival and apoptosis resistance in hippocampal neurons ( 19 ) and its knockout promotes a Parkinson's disease-like phenotype ( 20 ). DNA binding of NF- κ B/c-Rel is reduced in the substantia nigra and peripheral blood mononuclear cells of patients with Parkinson's disease ( 21 ). FAM161A (OMIM613596) is a microtubule-binding protein expressed throughout the photoreceptor inner segment, enriched in the photoreceptor base connecting cilia and basal body ( 22 , 23 ), which interacts with C8orf37 to promote the survival of photoreceptors ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Identification of microduplication in the chromosomal 2p16.1p15 region in an infant suffering from pulmonary arterial hypertension

Wang,

Zhang,

Zuo

et al. 2023

Front. Cardiovasc. Med.

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This study reports the first case of a patient with chromosomal 2p16.1p15 microduplication syndrome complicated by pulmonary arterial hypertension (PAH). A female infant was admitted to the hospital suffering from dyskinesia and developmental delay, and conventional echocardiography revealed an atrial septal defect (ASD), which was not taken seriously or treated at that time. Two years later, preoperative right heart catheterization for ASD closure revealed a mean pulmonary artery pressure (mPAP) of 45 mmHg. The mPAP was reduced, and the condition was stabilized after drug therapy. A genomic copy number duplication (3×) of at least 2.58 Mb in the 2p16.1p15 region on the paternal chromosome was revealed. Multiple Online Mendelian Inheritance in Man (OMIM) genes are involved in this genomic region, such as BCL11A, EHBP1, FAM161A, PEX13, and REL. EHBP1 promotes a molecular phenotypic transformation of pulmonary vascular endothelial cells and is thought to be involved in the rapidly developing PAH of this infant. Collectively, our findings contribute to the knowledge of the genes involved and the clinical manifestations of the 2p16.1p15 microduplication syndrome. Moreover, clinicians should be alert to the possibility of PAH and take early drug intervention when facing patients with 2p16.1p15 microduplications.

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Section: Discussionmentioning

confidence: 99%

Case Report: Identification of microduplication in the chromosomal 2p16.1p15 region in an infant suffering from pulmonary arterial hypertension

Wang,

Zhang,

Zuo

et al. 2023

Front. Cardiovasc. Med.

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“…T lymphocytes in particular have been implicated in the pathogenesis of α-synucleinopathies, with increased numbers observed in PD brains at postmortem [19], and peripheral T lymphocytes from people with PD are reactive against α-synuclein peptides [20,21]. Peripheral blood mononuclear cells from people with PD have also implicated abnormalities in the inflammation-associated transcription factor nuclear factor kappa B (NF-kB), in particular, loss of NK-kB/c-Rel anti-inflammatory and neuroprotective activity [22].…”

Section: Cytokines and Chemokinesmentioning

confidence: 99%

“…Enhanced activity of the multifunctional kinase enzyme LRRK2 in microglia is an important link between α-synuclein exposure, TLR2, and the release of proinflammatory cytokines (TNF-α and IL-6), through modulation of NFATc2 [57,118]. Reduced DNA-binding activity of the transcription factor NF-kB/c-Rel may also contribute to the perpetuation of inflammation in α-synucleinopathies [22].…”

Section: Contribution Of Inflammatory and Related Immune System Compo...mentioning

confidence: 99%

Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

Loveland,

Yu,

Churilov

et al. 2023

IJMS

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Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson’s disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development.

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TGF-β1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson’s disease models and patients

Zhuo,

Li,

et al. 2024

Military Med Res

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Background Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. Methods We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. Results A functional assay identified that transforming growth factor-β1 (TGF-β1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. Conclusions These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD.

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

Cited by 3 publications

References 74 publications

Case Report: Identification of microduplication in the chromosomal 2p16.1p15 region in an infant suffering from pulmonary arterial hypertension

Case Report: Identification of microduplication in the chromosomal 2p16.1p15 region in an infant suffering from pulmonary arterial hypertension

Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review

TGF-β1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson’s disease models and patients

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