Since protein aggregation formation is always associated with neuroinflammation, the overwhelming presence of cytokines (IL1B, TNF, MIF, CCL2, IL18, IL27, lymphotoxin, IL33, IFNG, IgG, and C5), inflammatory mediator (PTGS2/COX2), transmembrane receptors mediating innate immunity (CD14, TLR4, and CD163), transcription regulators (TP53, HIF1A, NFKB, and STAT3), post-transcriptional gene regulators (mir-155 and miR-155-5p), and purinergic receptor for macrophage lysis (P2RX7) as the top-ranked upstream regulators substantiate that neuroinflammation is a hallmark of synucleinopathy in the brain. The gene discussed is TNF; the disease is synucleinopathy.