α-Synuclein orchestrates Th17 responses as antigen and adjuvant in Parkinson’s disease

• DOI: 10.1186/s12974-025-03359-w
• Publication Date: 2025-02-11T16:08:57Z
• Authors: Emi Furusawa-Nishii; Bataa Solongo; Kou Rai; Soichiro Yoshikawa; Asako Chiba; Ayami Okuzumi; Shin-ichi Ueno; Yasunobu Hoshino; Yoko Imamichi-Tatano; Haruka Kimura; Taku Hatano; Nobutaka Hattori; Sachiko Miyake
• Keywords: Synucleinopathies

Recently, the role of T cells in pathology α-synuclein (αS)-mediated neurodegenerative disorders called synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy, has attracted increasing attention. Although existence αS-specific immunogenicity post-translationally modified αS fragment have been reported PD DLB, key cellular subset associated progression its induction mechanism remain largely unknown. Peripheral blood mononuclear (PBMCs) from synucleinopathy patients healthy controls were cultured presence peptide pools. Cytokine analysis using culture supernatants revealed that C-terminal peptides a phosphorylated serine 129 residue (pS129), feature pathological aggregates, promoted production IL-17A, IL-17F, IL-22, IFN-γ IL-13 compared controls. In pS129 peptide-reactive cases, Ki67 expression was increased CD4 but not CD8 cells, intracellular cytokine staining assay peptide-specific Th1 Th17 cells. The responses, demonstrated positive correlation Movement Disorder Society-Unified Disease Rating Scale (MDS-UPDRS) Part III scores. A similar observed for IL-17A levels supernatant PBMCs duration < 10 years. Interestingly, enhanced responses to uniquely found among suggesting are amplified by certain mechanisms patients. To investigate such mechanisms, we analyzed Th17-inducible capacity αS-exposed dendritic (DCs). vitro stimulation aggregates generated DCs IL-6 IL-23 through signaling TLR4 spliced X-box binding protein-1 (XBP1s). fact, plasma, XBP1s ratio type 2 conventional those Here, propose importance underlying inducing responses. These findings may provide novel therapeutic strategies prevent development suppression TLR4-XBP1s-IL-23 DCs.