Alpha-synuclein dynamics bridge Type-I Interferon response and SARS-CoV-2 replication in peripheral cells

Area of Science:

• Neuroimmunology
• Virology
• Molecular Biology

Background:

• Alpha-synuclein (α-syn) has a complex role in viral infections, including SARS-CoV-2, impacting both cell toxicity and innate immunity.
• While α-syn's role in neural cells is well-studied, its function in peripheral cells during viral infections remains less understood.

Purpose of the Study:

• To investigate the role of alpha-synuclein (α-syn) conformations in the peripheral innate immune response to SARS-CoV-2 infection.
• To elucidate the relationship between α-syn multimerization, Type-I Interferon (IFN) signaling, and viral replication.

Main Methods:

• Real-time quantitative PCR (qPCR) to measure gene expression.
• Immunofluorescence and Western blot assays to analyze α-syn protein levels and conformations.
• Cell culture experiments with epithelial and endothelial cells exposed to SARS-CoV-2, α-syn monomers, and IFN-β.

Main Results:

• SARS-CoV-2 infection upregulated α-syn in peripheral cells as part of a Type-I Interferon (IFN)-related response, primarily involving α-syn multimers.
• Excess α-syn monomers promoted viral replication and reduced IFN-Stimulated Genes (ISGs) by decreasing α-syn multimers.
• IFN-β administration counteracted these effects, hindering viral replication and restoring ISGs and α-syn multimerization without toxicity.

Conclusions:

• Dynamic α-syn conformations are crucial for the innate immune response against SARS-CoV-2 in peripheral cells.
• The promotion of non-toxic α-syn multimers is a Type-I IFN-mediated mechanism that helps suppress viral replication.
• Further research is needed to confirm these findings in neuronal cells and animal models.