Journal article
Aggregated alpha-synuclein transcriptionally activates pro-inflammatory canonical and non-canonical NF-KB signaling pathways in peripheral monocytic cells
Molecular immunology, v 154, pp 1-10
01 Feb 2023
PMID: 36571978
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by chronic neuroinflammation, loss of dopaminergic neurons in the substantia nigra, and in several cases accumulation of alpha-synuclein fibril (alpha-syn) containing Lewy-bodies (LBs). Peripheral inflammation may play a causal role in inducing and perpetuating neuroinflammation in PD and accumulation of fibrillar alpha-syn has been reported at several peripheral sites including the gut and liver. Peripheral fibrillar alpha-syn may induce activation of monocytes via recognition by toll like receptors (TLRs) and stimulation of downstream NF-KB signaling; however, the specific mechanism by which this occurs is not defined. In this study we utilized the THP-1 monocytic cell line to model the peripheral transcriptional response to preformed fibrillar (PFF) alpha-syn. Compared to monomeric alpha-syn, PFF alpha-syn displays overt inflammatory gene upregulation and pathway activation including broad pan-TLR signaling pathway activation and increases in TNF and IL1B gene expression. Notably, the non-canonical NF-KB signaling pathway gene and PD genome wide association study (GWAS) candidate NFKB2 was upregulated. Additionally, non canonical NF-KB activation-associated RANK and CD40 pathways were also upregulated. Transcriptional phenotype analysis suggests PFFs induce transcriptional programs associated with differentiation of monocytes towards macrophages and osteoclasts via non-canonical NF-KB signaling as a potential mechanism in which myeloid/monocyte cells may contribute to peripheral inflammation and pathogenesis in PD.
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Details
- Title
- Aggregated alpha-synuclein transcriptionally activates pro-inflammatory canonical and non-canonical NF-KB signaling pathways in peripheral monocytic cells
- Creators
- Frank Bearoff - Drexel UniversityDhruva Dhavale - Washington University in St. LouisPaul Kotzbauer - College Station Medical CenterSandhya Kortagere - Drexel University
- Publication Details
- Molecular immunology, v 154, pp 1-10
- Publisher
- Elsevier
- Number of pages
- 10
- Grant note
- Drexel Coulter Translational Fund NS110436 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000914994200001
- Scopus ID
- 2-s2.0-85145678830
- Other Identifier
- 991020548386204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Immunology