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

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.