PRMT1/Hmt1 drives α-synuclein aggregate dissolution through a catalysis-independent pathway

Abstract

Protein homeostasis, the balance between protein folding, function, and clearance, is essential for cellular health, and its disruption is a hallmark of many neurodegenerative diseases, including Parkinsons disease. Arginine methylation, carried out by enzymes like Hmt1 in yeast and PRMT1 in humans, is best known for regulating transcription, translation, apoptosis and pre-mRNA splicing. In this study, we reveal a surprising, non-canonical role for these methyltransferases in controlling the aggregation and toxicity of -synuclein, a protein lacking arginine and implicated in Parkinsons disease pathology. We find that under oxidative stress, Hmt1 and PRMT1 relocate from the nucleus into the cytoplasm. Using genetic, biochemical and imaging assays in yeast and mammalian cells, we observe that Hmt1/PRMT1 dissolve aggregates, promotes their removal through the ubiquitin-proteasome system, and reduces -synuclein toxicity. Importantly, this activity does not require the classical methyltransferase function. Catalytically inactive mutants and a specific PRMT1 inhibitor both enhance aggregate clearance and improve cell survival. Together, our findings uncover an unexpected function for Hmt1 and PRMT1 in maintaining protein quality under stress, expanding our understanding of how cells cope with toxic protein assemblies and pointing to new directions for therapeutic strategies in protein aggregation disorders.