Aggregated alpha-synuclein transcriptionally activates pro-inflammatory canonical and non-canonical NF-κB signaling pathways in peripheral monocytic cells

Frank Bearoff, Dhruva Dhavale, Paul Kotzbauer, Sandhya Kortagere

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 (α-syn) containing Lewy-bodies (LBs). Peripheral inflammation may play a causal role in inducing and perpetuating neuroinflammation in PD and accumulation of fibrillar α-syn has been reported at several peripheral sites including the gut and liver. Peripheral fibrillar α-syn may induce activation of monocytes via recognition by toll-like receptors (TLRs) and stimulation of downstream NF-κB 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) α-syn. Compared to monomeric α-syn, PFF α-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-κB signaling pathway gene and PD genome wide association study (GWAS) candidate NFKB2 was upregulated. Additionally, non-canonical NF-κB 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-κB signaling as a potential mechanism in which myeloid/monocyte cells may contribute to peripheral inflammation and pathogenesis in PD.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalMolecular Immunology
Volume154
DOIs
StatePublished - Feb 2023

Keywords

  • Alpha-synuclein
  • Monocytes
  • Non-canonical NF-κB signaling
  • Peripheral inflammation
  • Preformed fibrils

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