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

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