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

Parkinson’s Disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra due to Lewy body aggregates, primarily composed of misfolded alpha-synuclein (αSyn). While PD progression is thought to be driven by a prion-like spread of αSyn aggregates between neurons, the role of astrocytes remains unclear. Observations of αSyn pathology in PD patient astrocytes suggest their potential involvement in processing aggregates. To investigate this, we studied astrocytes’ interactions with αSyn pre-formed fibrils (PFFs) and their effects in astrocyte-neuron co-cultures on the spread of seed-competent αSyn. Primary astrocytes quickly internalized and degraded αSyn PFFs. However, degradation was significantly hindered by lysosome-compromising agents like chloroquine, Leupeptin, or CA-074. Adding astrocytes to neuron cultures reduced endogenous αSyn aggregation, indicating their role in mitigating αSyn pathology. When lysosome efficiency in astrocytes was compromised, their anti-seeding effect diminished. Moreover, lysosome-compromised astrocytes preloaded with αSyn PFFs enhanced αSyn pathology in neurons, whereas unimpaired astrocytes did not. These findings suggest astrocytes can modulate and contribute to αSyn pathology spread, playing a significant role in PD pathogenesis.