P2X7 Receptor Signalling as a Danger-Amplifying Hub in Lewy Body Diseases

Background: Lewy body diseases (LBD), encompassing Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterised by pathological α-synuclein (αSyn) aggregation, glial dysfunction and a lack of disease-modifying therapies. Converging evidence from α-synucleinopathy models, human neurodegenerative tissue and purinergic target-engagement studies implicates the glial ATP-gated P2X7 receptor (P2X7R) as a potential regulator of inflammatory and proteostatic stress.Main body: This review evaluates P2X7R as a candidate danger-amplifying hub in LBD. We propose that αSyn-rich, ATP-enriched microenvironments may shift glial P2X7R signalling from surveillance and clearance towards maladaptive effector programmes involving excitotoxic vulnerability, NF-κB/MAPK activation, inflammasome engagement, autophagic-lysosomal dysfunction and altered extracellular vesicle biology. We further consider human post-mortem, positron emission tomography (PET) imaging and preclinical evidence, highlighting that direct LBD-specific evidence remains limited and that P2X7R should be interpreted as a context-dependent glial effector receptor rather than a generic marker of inflammation. Conclusions: This framework provides a testable model in which chronic P2X7R activation may contribute to non-cell-autonomous neuronal injury and impaired αSyn handling. P2X7R therefore represents a promising but incompletely validated therapeutic target in LBD. Future studies should prioritise human validation, PET-based disease staging, multicellular αSyn models with cell-type-specific P2RX7 manipulation, and biomarker strategies that distinguish receptor availability from functional target engagement.