hnRNPA1 orchestrates multi-layered regulation of SNCA expression

Abstract Abnormal accumulation of alpha-synuclein (SNCA) is a hallmark of Parkinson’s disease (PD), yet the molecular mechanisms governing SNCA expression remain incompletely understood. The SNCA 3' untranslated region (3'UTR) plays a critical regulatory role, with linkage disequilibrium suggesting its involvement in sporadic PD. Analysis of SNCA 3'UTR isoforms revealed that longer variants exhibit increased nuclear retention, form nuclear speckles, decay more rapidly, produce less protein, and preferentially localize to the soma rather than axons. Mass spectrometry identified heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) as a key regulator of alternative polyadenylation (APA), promoting longer SNCA 3'UTR isoforms. hnRNPA1 selectively binds proximal and distal regions of the SNCA 3'UTR but not the 5'UTR or coding sequence. Functional studies demonstrated that hnRNPA1 enhances SNCA transcription while reducing nucleocytoplasmic shuttling of longer 3'UTR isoforms, destabilizes shorter transcripts, and restricts axonal transport of longer variants. At the protein level, hnRNPA1 decreases SNCA expression by increasing proteasomal degradation and autophagic flux. These findings establish hnRNPA1 as a multifaceted regulator of SNCA, integrating transcriptional and post-transcriptional control via APA, mRNA stability, subcellular transport, and protein turnover.