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<p>Intracellular accumulation of α-synuclein (αSyn) aggregates is a hallmark of synucleinopathies, such as Parkinson’s disease (PD) and multiple system atrophy (MSA). In MSA, αSyn aggregates form glial cytoplasmic inclusions (GCIs) in oligodendrocytes, despite their low expression of αSyn. Here, we demonstrate that neuron-to-oligodendrocyte propagation of αSyn, via Toll-like receptor 2 (TLR2) contributes to GCI formation. Male transgenic mice expressing the A53T mutant human αSyn exclusively in neurons, and the preformed fibril injection model exhibited MSA-like pathology, including GCI formation, gliosis, and neuroinflammation in the white matter. Notably, administration of NM-101, an anti-TLR2 antibody, significantly alleviated these pathological features. Transcriptome analyses revealed demyelination-related features in MSA oligodendrocytes and experimental models. Elevated <i>TLR2</i> expression in MSA oligodendrocytes inversely correlated with <i>MBP</i> expression, and the correlation was absent in PD. In the transgenic mouse model, NM-101 administration rescued the demyelination phenotype. These findings highlight anti-TLR2 immunotherapy as a potential disease-modifying approach for MSA.</p>

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Anti-TLR2 immunotherapy modulates neuron-to-oligodendrocyte propagation of α-synuclein in mouse and human models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月30日

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  • Eun-Jin Bae,
  • Sangwoo Ham,
  • Yeonwoo William Jeong,
  • Woo Seung Yang,
  • Jimin Shin,
  • Won-Jae Lee,
  • Woo Jung Ahn,
  • Ye-Seul Yoon,
  • He-Jin Lee,
  • Sang Hwan Lee,
  • Sung-Hye Park,
  • Seung-Jae Lee

摘要

Intracellular accumulation of α-synuclein (αSyn) aggregates is a hallmark of synucleinopathies, such as Parkinson’s disease (PD) and multiple system atrophy (MSA). In MSA, αSyn aggregates form glial cytoplasmic inclusions (GCIs) in oligodendrocytes, despite their low expression of αSyn. Here, we demonstrate that neuron-to-oligodendrocyte propagation of αSyn, via Toll-like receptor 2 (TLR2) contributes to GCI formation. Male transgenic mice expressing the A53T mutant human αSyn exclusively in neurons, and the preformed fibril injection model exhibited MSA-like pathology, including GCI formation, gliosis, and neuroinflammation in the white matter. Notably, administration of NM-101, an anti-TLR2 antibody, significantly alleviated these pathological features. Transcriptome analyses revealed demyelination-related features in MSA oligodendrocytes and experimental models. Elevated TLR2 expression in MSA oligodendrocytes inversely correlated with MBP expression, and the correlation was absent in PD. In the transgenic mouse model, NM-101 administration rescued the demyelination phenotype. These findings highlight anti-TLR2 immunotherapy as a potential disease-modifying approach for MSA.