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

ABSTRACT: The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of ?-synuclein. Clearance of extracellular ?-synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of ?-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 ?-synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary ?-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 ?-synuclein aggregates by astrocytes. Our findings showed that astrocytes take up ?-synuclein preformed fibrils (pffs) through dynamin-dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon ?-synuclein pffs exposure. Specifically, we found that clusterin interacts with ?-synuclein pffs in the extracellular compartment and the clusterin/?-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 ?-synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno-associated virus- and the ?-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 ?-synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology.

SUBMITTER: Filippini A 

PROVIDER: S-EPMC7821254 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature