Extracellular clusterin limits the uptake of α-synuclein fibrils by murine and human astrocytes

The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of alpha-synuclein. Clearance of extracellular alpha-synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of alpha-synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in the extracellular compartment. Among these, clusterin, a glycoprotein associated with Alzheimer's disease, binds alpha-synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary alpha-synuclein. In this study, using murine primary astrocytes with clusterin genetic deletion, human-induced pluripotent stem cell (iPSC)-derived astrocytes with clusterin silencing and two animal models relevant for PD we explore how clusterin affects the clearance of alpha-synuclein aggregates by astrocytes. Our findings showed that astrocytes take up alpha-synuclein preformed fibrils (pffs) through dynamin-dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon alpha-synuclein pffs exposure. Specifically, we found that clusterin interacts with alpha-synuclein pffs in the extracellular compartment and the clusterin/alpha-synuclein complex can be internalized by astrocytes. Mechanistically, using clusterin knock-out primary astrocytes and clusterin knock-down hiPSC-derived astrocytes we observed that clusterin limits the uptake of alpha-synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno-associated virus- and the alpha-synuclein pffs- injected mouse model, suggesting a crucial role of this chaperone in the pathogenesis of PD. Overall, our observations indicate that clusterin can limit the uptake of extracellular alpha-synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology.

Automated summary

The progressive neuropathological damage in Parkinson's disease is believed to be related to the spread of aggregated forms of alpha-synuclein. Clearance of extracellular alpha-synuclein by neurons may be a key mechanism to control its concentration. Clusterin, a glycoprotein associated with Alzheimer's disease, interacts with alpha-synuclein aggregates and limits their uptake by astrocytes, which may contribute to the spreading of Parkinson's pathology.