Reactive Astrocytes Drive Extracellular Acidification to Mediate α-Synuclein Neurodegeneration

Abstract Astrocytes are increasingly recognized as key players in neurodegeneration 1–3 , yet the molecular mechanisms by which they drive disease remain elusive. Here, we uncover a fundamental pathway in which reactive astrocytes fuel neurodegeneration in α-synucleinopathies—including Dementia with Lewy bodies and Parkinson’s disease dementia—by acidifying the brain’s extracellular environment. We demonstrate that both human patient tissue and a gut-to-brain α-synuclein mouse model exhibit accumulation of reactive astrocytes and extracellular acidosis. Mechanistically, we show that astrocytic lysosomal exocytosis releases acidic contents, driving a drop in pH that activates neuronal acid-sensing ion channel 1a (ASIC1a), resulting in neuronal loss and behavioral decline. Blocking this pathway—either by inhibiting astrocytic lysosomal exocytosis or genetically or pharmacologically targeting neuronal ASIC1a—mitigates pathology and rescues neurodegenerative phenotypes in vivo. These findings provide a conceptual advance by establishing a mechanistic link between glial inflammation, acid-base homeostasis, and neuronal vulnerability, and suggest that targeting astrocyte-driven acidification or ASIC1a signaling could offer new avenues for disease modification in α-synucleinopathies.