Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinsons-like gut pathology

Mackie, P. M.; Koshy, J.; Bhogade, M.; Hammoor, T.; Hachmeister, W.; Lloyd, G. M.; Paterno, G.; Bolen, M.; Tansey, M. G.; Giasson, B.; Khoshbouei, H.

doi:10.1101/2023.10.24.563832

bioRxiv · 10.1101/2023.10.24.563832

Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinsons-like gut pathology

Mackie, P. M.·Koshy, J.·Bhogade, M.·Hammoor, T.·Hachmeister, W.·Lloyd, G. M.·Paterno, G.·Bolen, M.·Tansey, M. G.·Giasson, B.·Khoshbouei, H.

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Abstract

Deposition of misfolded -synuclein (syn) 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 Parkinsons Disease (PD), but the cellular and molecular mechanisms that shape enteric histopathology and dysfunction are poorly understood. Here, we demonstrate that ENS-resident macrophages, which play a critical role in maintaining ENS homeostasis, initially respond to enteric neuronal syn 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 syn-induced gut dysfunction. Internalization of syn led to increased endo-lysosomal stress that resulted in macrophage exhaustion and temporally correlated with the progression of ENS pathology. These novel findings highlight the importance of enteric neuron-macrophage interactions in removing toxic protein aggregates that putatively shape the earliest stages of PD in the periphery.

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Mackie, P. M., Koshy, J., Bhogade, M., Hammoor, T., Hachmeister, W., Lloyd, G. M., Paterno, G., Bolen, M., Tansey, M. G., Giasson, B., Khoshbouei, H.. 2023-10-28. Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinsons-like gut pathology. https://doi.org/10.1101/2023.10.24.563832

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