Complement C1q-dependent engulfment of alpha-synuclein induces ENS-resident macrophage exhaustion and accelerates Parkinson's-like gut pathology.
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
28 Oct 2023
28 Oct 2023
Historique:
pubmed:
14
11
2023
medline:
14
11
2023
entrez:
14
11
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37961460
doi: 10.1101/2023.10.24.563832
pmc: PMC10634831
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NINDS NIH HHS
ID : F30 NS129283
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001427
Pays : United States
Organisme : NCATS NIH HHS
ID : TL1 TR001428
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS071122
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS133384
Pays : United States
Déclaration de conflit d'intérêts
Competing interests None to declare.
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