Amyloid aggregates of α-Synuclein are hallmark of Parkinson’s Disease (PD) and related neurodegenerative diseases. α-Synuclein, being an non-canonical RNA-binding protein (RBP), associates with other RBPs within cytosolic RNA-protein granules to modulate mRNA-stability. Conversely, mRNA G-quadruplexes (rG4s) expedite α-Synuclein amyloidogenesis. However, spatiotemporal control on α-Synuclein amyloidogenesis by other RBPs remains unexplored. Here, we report that RNA-dependent cytosolic interaction with DEAD-box RNA-helicase DDX39A decelerates α-Synuclein amyloidogenesis. Viral infections transiently elevate rG4s in cytoplasm. Perturbing interactions between α Synuclein and DDX39A using viral rG4s from H1N1-influenza and SARS-CoV-2 genomes expedites intracellular amyloidogenesis. Conversely, DDX39A overexpression alleviates α-Synuclein amyloidogenesis in mouse primary neurons triggered by SARS-CoV-2 infection. We demonstrate that while DDX39A unwinds viral rG4s to mitigate α-Synuclein sol-gel transition, its reciprocal cooperative phase separation with α-Synuclein enhances the helicase’s rG4-unwinding activity. We propose that accelerated α-Synuclein amyloidogenesis represents a trade-off within this RNA–protein interaction equilibrium, contributing to the viral etiology of PD.