Intestinal Macrophages Modulate Brain Synucleinopathy in Parkinson’s Disease

Emerging evidence suggests that Parkinson’s disease (PD) may have its origin in the enteric nervous system (ENS), from where alpha-synuclein (αS) pathology spreads to the brain. Decades before the onset of motor symptoms, PD patients suffer from constipation and present with circulating T cells responsive to αS, suggesting that peripheral immune responses initiated in the ENS may be involved in the early stages of PD. However, cellular mechanisms that trigger αS pathology in the ENS and its spread along the gut-brain axis remain elusive. Here, we demonstrate that muscularis macrophages (ME-Macs), housekeepers of ENS integrity and intestinal homeostasis, modulate αS pathology and neurodegeneration in models of PD. ME-Macs contain misfolded αS, adopt a signature reflecting endolysosomal dysfunction, and modulate the expansion of T cells that travel from the ENS to the brain via the dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and CNS, prevents T cell expansion, and mitigates neurodegeneration and motor dysfunction, suggesting a role for ME-Macs as early cellular initiators of αS pathology along the gut-brain axis. Understanding these mechanisms could pave the way for early-stage biomarkers in PD.