Astrocytic lysosome deficits reduce alpha-synuclein degradation and induce the spread of pathology

Parkinson's Disease (PD) is a neurodegenerative disorder that results from a loss of dopaminergic neurons in the substantia nigra. A pathological hallmark of PD is proteinaceous inclusions called Lewy body aggregates, which consist primarily of misfolded neuronal alpha-synuclein (αSyn). PD pathology progression is thought to be driven by a prion-like spread of αSyn aggregates between adjacent neurons; however, the role of other cell types, such as pathology bearing astrocytes, in this process is still elusive. αSyn pathology has been observed in PD patient astrocytes, suggesting that astrocytes could be involved in the processing of aggregates. Therefore, we examined the interaction of astrocytes with αSyn pre-formed fibrils (PFFs) and explored how these cells might modulate the spread of seed-competent αSyn in astrocyte-neuron co-cultures. Isolated primary astrocytes rapidly internalized and degraded αSyn PFFs within hours of internalization. Upon exposure to lysosome compromising agents, such as chloroquine or cathepsin B inhibitors leupeptin or CA-074, degradation of αSyn PFFs was significantly reduced. The addition of astrocytes to primary neuron cultures reduced endogenous αSyn aggregation caused by exogenous αSyn PFFs, indicating that astrocytes may mitigate αSyn pathology in the brain. The addition of lysosome-compromised (LC) astrocytes to primary neuron cultures limited this anti-seeding effect. Finally, LC astrocytes, preloaded with PFFs and added to neuronal cultures, induced αSyn pathology in neurons, whereas unimpaired, PFF-preloaded astrocytes did not. These data suggest that astrocytes can modulate and contribute to the spread of αSyn pathology, significantly contributing to PD pathogenesis.