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<p>Deposition of misfolded α-synuclein (αsyn) in the enteric nervous system (ENS) is found in multiple neurodegenerative diseases. It is hypothesized that ENS synucleinopathy contributes to both the pathogenesis and non-motor morbidity in Parkinson’s Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we employ a fibrillar injection model of enteric synucleinopathy in male mice and demonstrate that ENS-resident macrophages, which play a critical role in maintaining ENS homeostasis, initially respond to enteric neuronal αsyn pathology by upregulating machinery for complement-mediated engulfment. Pharmacologic depletion of ENS-macrophages or genetic deletion of C1q enhanced enteric neuropathology. Conversely, C1q deletion ameliorated gut dysfunction, indicating that complement partially mediates αsyn-induced gut dysfunction. However, this C1q-dependent clearance mechanism diminished over time and its failure temporally correlated with the further increase in ENS pathology. These findings highlight the importance of enteric neuron-macrophage interactions in removing toxic protein aggregates that putatively shape the gastrointestinal manifestations of PD.</p>

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C1q-dependent clearance of alpha-synuclein allows macrophages to transiently limit enteric synucleinopathy in male mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月20日

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  • Phillip M. Mackie,
  • Joanne M. Koshy,
  • Mauli H. Bhogade,
  • Tristan Hammoor,
  • William Hachmeister,
  • Grace M. Lloyd,
  • Giavanna Paterno,
  • Mackenzie L. Bolen,
  • Andrea Merchak,
  • Malu Gamez-Tansey,
  • Benoit I. Giasson,
  • Habibeh Khoshbouei

摘要

Deposition of misfolded α-synuclein (αsyn) in the enteric nervous system (ENS) is found in multiple neurodegenerative diseases. It is hypothesized that ENS synucleinopathy contributes to both the pathogenesis and non-motor morbidity in Parkinson’s Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we employ a fibrillar injection model of enteric synucleinopathy in male mice and demonstrate that ENS-resident macrophages, which play a critical role in maintaining ENS homeostasis, initially respond to enteric neuronal αsyn pathology by upregulating machinery for complement-mediated engulfment. Pharmacologic depletion of ENS-macrophages or genetic deletion of C1q enhanced enteric neuropathology. Conversely, C1q deletion ameliorated gut dysfunction, indicating that complement partially mediates αsyn-induced gut dysfunction. However, this C1q-dependent clearance mechanism diminished over time and its failure temporally correlated with the further increase in ENS pathology. These findings highlight the importance of enteric neuron-macrophage interactions in removing toxic protein aggregates that putatively shape the gastrointestinal manifestations of PD.