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Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology
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 mechani...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634831/ https://www.ncbi.nlm.nih.gov/pubmed/37961460 http://dx.doi.org/10.1101/2023.10.24.563832 |
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author | Mackie, PM Koshy, J Bhogade, M Hammoor, T Hachmeister, W Lloyd, GM Paterno, G Bolen, M Tansey, MG Giasson, BI Khoshbouei, H |
author_facet | Mackie, PM Koshy, J Bhogade, M Hammoor, T Hachmeister, W Lloyd, GM Paterno, G Bolen, M Tansey, MG Giasson, BI Khoshbouei, H |
author_sort | Mackie, PM |
collection | PubMed |
description | 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 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. Internalization of αsyn 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. |
format | Online Article Text |
id | pubmed-10634831 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-106348312023-11-13 Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology Mackie, PM Koshy, J Bhogade, M Hammoor, T Hachmeister, W Lloyd, GM Paterno, G Bolen, M Tansey, MG Giasson, BI Khoshbouei, H bioRxiv Article 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 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. Internalization of αsyn 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. Cold Spring Harbor Laboratory 2023-10-28 /pmc/articles/PMC10634831/ /pubmed/37961460 http://dx.doi.org/10.1101/2023.10.24.563832 Text en https://creativecommons.org/licenses/by-nc/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Mackie, PM Koshy, J Bhogade, M Hammoor, T Hachmeister, W Lloyd, GM Paterno, G Bolen, M Tansey, MG Giasson, BI Khoshbouei, H Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology |
title | Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology |
title_full | Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology |
title_fullStr | Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology |
title_full_unstemmed | Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology |
title_short | Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson’s-like gut pathology |
title_sort | complement c1q-dependent engulfment of alpha-synuclein induces ens-resident macrophage exhaustion and accelerates parkinson’s-like gut pathology |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634831/ https://www.ncbi.nlm.nih.gov/pubmed/37961460 http://dx.doi.org/10.1101/2023.10.24.563832 |
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