DDX39A unwinds viral RNA G-quadruplexes to limit α-Synuclein amyloidogenesis.

Amyloid aggregates of α-Synuclein are hallmarks of Parkinson's disease (PD) and related neurodegenerative disorders. Literature suggests that mRNA G-quadruplexes (rG4s) bind to α-Synuclein, facilitating its amyloidogenesis. In parallel, α-Synuclein interacts with RNA-binding proteins (RBPs) within cytosolic RNA-protein granules to modulate mRNA stability. However, mechanisms by which α-Synuclein-interacting RBPs regulate its amyloidogenesis remain unexplored. Here, we report that rG4-dependent cytosolic interaction with the DEAD-box helicase DDX39A decelerates α-Synuclein amyloidogenesis. Notably, viral infections transiently elevate rG4s in the cytoplasm. Perturbing interactions between α-Synuclein and DDX39A using genomic rG4-sequences from H1N1 Influenza and SARS-CoV-2 expedites intracellular amyloidogenesis. Conversely, DDX39A overexpression alleviates α-Synuclein amyloidogenesis in SARS-CoV-2-infected primary neurons. We demonstrate that while DDX39A unwinds viral rG4s to mitigate α-Synuclein sol-gel transition, its cooperative phase separation with α-Synuclein enhances the helicase's rG4-unwinding activity. We propose that accelerated α-Synuclein amyloidogenesis reflects a trade-off within this RNA-protein equilibrium and might contribute to the viral etiology of PD.