Peripheral Modulators Of Neurodegeneration Along The Gut-brain Axis In Synucleinopathies (360G-Wellcome-328053_Z_25_Z)

The gut-brain axis and neuroinflammation are emerging as key players in early stages of Parkinson’s disease (PD), challenging the neuron-centric view that PD is confined to the brain. We recently identified gut-resident macrophages as early instigators of PD-related pathologies. Dysfunctional gut-resident macrophages lead to exacerbated alpha-synuclein aggregation–a hallmark of PD and other synculeinopathies–and propagation along the gut-brain axis, leading to region-specific neurodegeneration in the brain. Our findings unlock therapeutic and biomarker opportunities beyond the brain; however, a fundamental knowledge gap remains: how do peripheral neuroimmune interactions in the gut mediate alpha-synuclein pathology and region-specific brain neurodegeneration? We assembled an interdisciplinary team to dissect neuroimmune mechanisms and their interactions with disease-specific alpha- synuclein aggregates in gut and brain. Integrating whole-body clearing, multi- omics, spatial transcriptomics, in vivo proteomics, advanced microscopy, functional studies in mice, and mechanistic studies in human cells. We aim to understand gut-brain immune crosstalk and its role in alpha-synuclein pathology on a molecular, cell-to-cell and organism-wide level. Insights will redefine neuroimmune modelling in PD, establishing how peripheral neuroimmune interactions contribute to disease-relevant protein aggregation and selective neurodegeneration. By expanding the therapeutic focus beyond the brain, this work could transform early intervention and disease-modifying strategies for PD and related disorders.