Investigating the role of gut macrophages in mediating alpha-synuclein pathology in Parkinson’s disease

The gut-brain axis is at the heart of Parkinson’s disease (PD) etiology.

Pathological alpha-synuclein accumulates early in the gut, potentially affecting the enteric nervous system (ENS) and spreads to the brain.

However, we lack insights into how pathological alpha-synuclein affects ENS integrity and cellular mediators underlying their spread.

Here, I propose to study the role of a unique subset of gut macrophages (gMacs), the ENS-gMacs, that coordinate neuronal function in their unique ENS niche. I hypothesize that ENS-gMacs critically dependent on LRRK2 for alpha-synuclein clearance.

LRRK2 is a risk factor for PD, regulates alpha-synuclein clearance in macrophages and is highly enriched in ENS-gMacs compared to microglia and neurons.

First, using state-of-the-art single cell RNA and in-situ sequencing techniques I will examine how ENS-gMacs and microglia become dysfunctional in PD mouse models.

Second, using in vivo and in vitro tools, I will dissect whether mutant LRRK2 signaling in ENS-gMacs affects neuronal function and survival upon PD patient-derived pathological alpha-synuclein. Finally, I will investigate how ENS-gMacs contribute to alpha-synuclein pathology and spread.

Insights obtained will create new avenues to study neuroimmune pathways along gut-brain axis for the future, as well as novel targets for early therapeutic interventions in PD.