ALPHA-SYNUCLEIN DYNAMICS IN REACTIVE ASTROCYTES

Parkinson’s is a neurodegenerative disease characterised by the formation of $α-synuclein aggregates and dopaminergic neuron loss in the substantia nigra. Chronic inflammation in the brain is present in a wide range of neurodegenerative diseases, including Parkinson’s. While research has traditionally focussed on the neurons affected by degeneration, our work explores the role of astrocytes, mediators of inflammation in the brain. In response to inflammation, astrocytes become “reactive”, switching from a neurosupportive to neurotoxic phenotype. Although animal models of Parkinson’s have shown that these reactive astrocytes cause neurodegeneration, the functional alterations elicited by inflammation that lead to neuronal loss are yet to be fully understood. Using hiPSC-derived ventral-midbrain astrocytes, we have identified a novel response in reactive astrocytes where in vitro conditions recapitulating pro-inflammatory signals from activated microglia causes astrocytes to upregulate release of $α -synuclein. To identify the mechanisms governing this response we conducted a targeted membrane trafficking gene siRNA screen which revealed a number of exciting candidates including a component of the lysosomal V-ATPase. To validate this we further targeted this complex with shRNA and we found that the $α-synuclein release associated with astrocyte reactivity was further increased.
These findings show that astrocytes release $α-synuclein when reactive in response to neuroinflammation contributing to pathology in a previously unidentified way. This suggests that astrocyte involvement in synucleinopathy may extend beyond clearance of neuronally secreted protein. This release of endogenous $α-synuclein is upregulated by inhibition of proper lysosomal acidification, pointing to autolysosomal dysfunction as a causative mechanism.