HYDERABAD: A study by researchers at the CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, has identified a molecular mechanism through which RNA virus infections may accelerate the formation of amyloid clumps associated with Parkinson’s disease.
Published in Cell Reports, the study was conducted by Dr Swasti Raychaudhuri’s laboratory at CCMB. It examines how infections caused by RNA viruses, including influenza and Covid-19, may trigger molecular changes linked to neurodegeneration and identifies a cellular mechanism that can counter the process.
Several studies have reported an association between influenza and Covid-19 infections and an increased risk of neurodegenerative diseases such as Parkinson’s. However, the molecular mechanisms underlying the association have remained unclear.
The CCMB study focuses on α-Synuclein, a protein that forms amyloid deposits in the brains of people with Parkinson’s disease. Amyloids are abnormal clumps formed when proteins aggregate and can interfere with communication between neurons and affect their functioning.
Researchers found that RNA viruses carry their genetic material in specific three-dimensional structures known as RNA G-quadruplexes, or rG4s. When a virus infects a cell, these structures can bind to α-Synuclein and accelerate the formation of amyloid clumps, the study found.
The researchers also identified a cellular defence mechanism that acts against both viral replication and amyloid formation.
Cell’s own defence
During infection, a helicase protein called DDX39A, which is normally located in the cell nucleus, is released into the cytoplasm. It binds to both α-Synuclein and viral rG4 structures.
DDX39A then unwinds the viral RNA structures, making it harder for the virus to replicate and reducing the viral load inside the cell. At the same time, dismantling the secondary structure of viral RNA slows the formation of α-Synuclein amyloids.
“The virus fails to replicate with its RNA structures dismantled, and thus, the viral load in the cells decreases. At the same time, the unwinding of viral RNA’s secondary structure effectively slows down α-Synuclein amyloid formation,” said Aanchal, a first author of the study.
The researchers stressed, however, that the interaction between viruses, cellular defence mechanisms and amyloid formation is complex. Different cellular conditions can influence the balance between these processes.
The findings do not suggest that every viral infection will increase amyloid formation or lead to neurodegenerative disease. Instead, the researchers point to the possibility that repeated viral infections could influence the balance of these molecular processes.
The study adds to research examining how infections may interact with processes involved in neurodegeneration. By identifying the role of viral RNA structures and the protective function of DDX39A, the researchers have highlighted a possible molecular pathway through which infections could influence brain health over longer periods.
Dr Raychaudhuri’s laboratory is now studying how these molecular interactions may operate over longer periods and under different conditions, and whether routine viral infections could potentially contribute to processes associated with Parkinson’s disease years later.
