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<p>Synucleinopathies are age-related neurological disorders which include dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and multiple system atrophy (MSA). A hallmark of these diseases is the pathological accumulation of α-synuclein aggregates, along with sustained neuroinflammatory responses. Recent studies have demonstrated the existence of structurally distinct α-synuclein aggregates in this group of the diseases. While the correlation between specific forms of α-synuclein and distinct pathological characteristics has been extensively studied, their relationship to neuroinflammation remains elusive. Here, we examined the effects of structurally distinct α-synuclein polymorphs on microglial neuroinflammation. Human induced pluripotent stem cells (iPSCs)-derived microglia (iMicroglia, iMG) were treated with α-synuclein polymorphs including EGCG stabilized α-synuclein oligomers (EO), kinetically stable α-synuclein oligomers (KSO), dopamine stabilized α-synuclein oligomers (DO), α-synuclein preformed fibrils (PFF), sonicated α-synuclein preformed fibrils (sPFF), and matured α-synuclein fibrils (Fib). Microglial gene expressions were accessed by transcriptome analysis and Toll-like receptor agonist activities were determined by HEK-Blue TLR reporter assay. Exposures to kinetically stable α-synuclein oligomers and matured α-synuclein fibrils induced the expression of microglial cytokines and chemokines, while other species did not. Microglial transcriptome analysis yielded that all polymorphs commonly induce toll-like receptor (TLR) signaling cascade despite differential transcriptomic phenotypes. Among structurally distinct α-synuclein polymorphs, live cell TLR reporter assay showed that kinetically stable α-synuclein oligomers induce the activities of TLR2 and 4, and sonicated α-synuclein preformed fibril TLR4, relative to the control. These results suggest that structurally distinct α-synuclein polymorphs have likewise distinct neuroinflammatory properties.</p>

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Differential microglial responses to structurally distinct alpha-synuclein polymorphs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • Katherine Chang,
  • Jina Kim,
  • Michiyo Iba,
  • Jae-Hyeon Park,
  • Alexandria Beilina,
  • Zulfeqhar A. Syed,
  • Valentina Baena,
  • Liam Horan-Portelance,
  • Mark R. Cookson,
  • Sungyong You,
  • Changyoun Kim

摘要

Synucleinopathies are age-related neurological disorders which include dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and multiple system atrophy (MSA). A hallmark of these diseases is the pathological accumulation of α-synuclein aggregates, along with sustained neuroinflammatory responses. Recent studies have demonstrated the existence of structurally distinct α-synuclein aggregates in this group of the diseases. While the correlation between specific forms of α-synuclein and distinct pathological characteristics has been extensively studied, their relationship to neuroinflammation remains elusive. Here, we examined the effects of structurally distinct α-synuclein polymorphs on microglial neuroinflammation. Human induced pluripotent stem cells (iPSCs)-derived microglia (iMicroglia, iMG) were treated with α-synuclein polymorphs including EGCG stabilized α-synuclein oligomers (EO), kinetically stable α-synuclein oligomers (KSO), dopamine stabilized α-synuclein oligomers (DO), α-synuclein preformed fibrils (PFF), sonicated α-synuclein preformed fibrils (sPFF), and matured α-synuclein fibrils (Fib). Microglial gene expressions were accessed by transcriptome analysis and Toll-like receptor agonist activities were determined by HEK-Blue TLR reporter assay. Exposures to kinetically stable α-synuclein oligomers and matured α-synuclein fibrils induced the expression of microglial cytokines and chemokines, while other species did not. Microglial transcriptome analysis yielded that all polymorphs commonly induce toll-like receptor (TLR) signaling cascade despite differential transcriptomic phenotypes. Among structurally distinct α-synuclein polymorphs, live cell TLR reporter assay showed that kinetically stable α-synuclein oligomers induce the activities of TLR2 and 4, and sonicated α-synuclein preformed fibril TLR4, relative to the control. These results suggest that structurally distinct α-synuclein polymorphs have likewise distinct neuroinflammatory properties.