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Pneumonia outbreak in the city of Wuhan, China, prompted the finding of a novel strain of severe acute respiratory syndrome virus (SARS-CoV-2). Here, we discuss potential long-term consequences of SARS-CoV-2 infection, and its possibility to cause permanent damage to the immune system and the central nervous system. Advanced chronological age is one of the main risk factors for the adverse outcomes of COVID-19, presumably due to immunosenescence and chronic low-grade inflammation, both characteristic of the elderly. The combination of viral infection and chronic inflammation in advanced chronological age might cause multiple detrimental unforeseen consequences for the predisposition and severity of neurodegenerative diseases and needs to be considered so that we can be prepared to deal with future outcomes of the ongoing pandemic.

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A BS TRACT: Background: The cellular prion protein (PrP C ) is a membrane-bound, multifunctional protein mainly expressed in neuronal tissues. Recent studies indicate that the native trafficking of PrP C can be misused to internalize misfolded amyloid beta and α-synuclein (aSyn) oligomers. Objectives: We define PrP C 's role in internalizing misfolded aSyn in α-synucleinopathies and identify further involved proteins. Methods: We performed comprehensive behavioral studies on four transgenic mouse models (ThySyn and ThySynPrP00, TgM83 and TgMPrP00) at different ages. We developed PrP C -(over)-expressing cell models (cell line and primary cortical neurons), used confocal laser microscopy to perform colocalization studies, applied mass spectrometry to identify interactomes, and determined disassociation constants using surface plasmon resonance (SPR) spectroscopy. Results: Behavioral deficits (memory, anxiety, locomotion, etc.), reduced lifespans, and higher oligomeric aSyn levels were observed in PrP C -expressing mice (ThySyn and TgM83), but not in homologous Prnp ablated mice (ThySynPrP00 and TgMPrP00). PrP C colocalized with and facilitated aSyn (oligomeric and monomeric) internalization in our cell-based models. Glimepiride treatment of PrP Coverexpressing cells reduced aSyn internalization in a dosedependent manner. SPR analysis showed that the binding affinity of PrP C to monomeric aSyn was lower than to oligomeric aSyn. Mass spectrometry-based proteomic studies identified clathrin in the immunoprecipitates of PrP C and aSyn. SPR was used to show that clathrin binds to recombinant PrP, but not aSyn. Experimental disruption of clathrincoated vesicles significantly decreased aSyn internalization. Conclusion: PrP C 's native trafficking can be misused to internalize misfolded aSyn through a clathrin-based mechanism, which may facilitate the spreading of pathological aSyn. Disruption of aSyn-PrP C binding is, therefore, an appealing therapeutic target in α-synucleinopathies.