Parkinson's disease is driven by the spread of misfolded α-synuclein through the brain. The most evident symptoms result from the death and dysfunction of motor neurons, caused by the presence of misfolded α-synuclein. Once α-synuclein misfolds, it is capable of inducing other molecules of α-synuclein to misfold in the same way, and this dysfunction can slowly spread from cell to cell. In recent years, researchers have shown that in a sizable fraction of Parkinson's disease cases misfolded α-synuclein first emerges in the intestines and then spreads to the brain. Here, researchers uncover more of the mechanisms by which this transmission takes place, with an eye to finding ways to intervene in the earliest stages of the condition in order to prevent later consequences.
Emerging evidence suggests that Parkinson's disease (PD) may have its origin in the enteric nervous system (ENS), from where α-synuclein (αS) pathology spreads to the brain. Decades before the onset of motor symptoms, patients with PD 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 through the dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and central nervous system, 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.
Link: https://doi.org/10.1038/s41586-025-09984-y
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