Anti-TLR2 immunotherapy modulates neuron-to-oligodendrocyte propagation of α-synuclein in mouse and human model
Publication date: 30/01/2026
Authors: Eun-Jin B, Sangwoo H, Yeonwoo W J, Woo Seung Y, Jimin S, Won-Jae L, Woo Jung A, Ye-Seul Yoon, He-Jin L, Sang Hwan L, Sung-Hye P & Seung-Jae L
Journal: Nature Communications
Commentary: The study provides compelling evidence that the intracellular accumulation of α-synuclein (αSyn) in glial cytoplasmic inclusions (GCIs) of oligodendrocytes is driven, at least in part, by neuron-to-oligodendrocyte propagation via Toll-like receptor 2 (TLR2). This mechanism offers an elegant explanation for how oligodendrocytes, which normally express very low levels of αSyn, become sites of pathological aggregation in multiple system atrophy (MSA). Using A53T αSyn transgenic mice and preformed fibril models, Eun-Jin and colleagues effectively recapitulate key pathological hallmarks of MSA, including GCI formation, gliosis, and neuroinflammation, demonstrating the translational relevance of these models. Importantly, the study shows that targeting TLR2 with the monoclonal antibody NM-101 can substantially mitigate GCI formation and reduce inflammation. Notably, it also rescues demyelination. Transcriptome analyses reveal that TLR2 upregulation in oligodendrocytes inversely correlates with MBP expression in MSA—but not in Parkinson’s disease—further strengthening the disease-specific relevance of this pathway. These findings suggest that TLR2 not only facilitates αSyn propagation but also contributes directly to oligodendrocyte dysfunction and myelin loss. Overall, the work provides a strong rationale for developing anti-TLR2 immunotherapy as a disease-modifying strategy for MSA. By linking neuron-to-glia αSyn spread to oligodendrocyte pathology and showing that pharmacological intervention can reverse demyelination, the study opens new avenues for therapeutic intervention in synucleinopathies. Future studies exploring long-term efficacy, safety, and potential combination with other anti-αSyn strategies will be critical for translating these findings to clinical applications.
Commented by: Giuseppina Natale
DOI: https://doi.org/10.1038/s41467-026-68870-x
