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.
Extracellular clusterin limits the uptake of α-synuclein fibrils by murine and human astrocytes / Filippini, Alice; Mutti, Veronica; Faustini, Gaia; Longhena, Francesca; Ramazzina, Ileana; Rizzi, Federica; Kaganovich, Alice; Roosen, Dorien A; Landeck, Natalie; Duffy, Megan; Tessari, Isabella; Bono, Federica; Fiorentini, Chiara; Greggio, Elisa; Bubacco, Luigi; Bellucci, Arianna; Missale, Mariacristina; Cookson, Mark R; Gennarelli, Massimo; Russo, Isabella. - In: GLIA. - ISSN 0894-1491. - (2020). [10.1002/glia.23920]
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