Parkinson’s disease (PD) is the most common progressive neurodegenerative movement disorder. PD has exceedingly complex aetiology with ~85-95% of cases being idiopathic. To determine what molecular mechanisms might underpin regional vulnerability to PD, we employed total and targeted (capturing 45 Mbp of the PD-focused transcriptome) RNA sequencing. We sequenced post-mortem brain tissue across 3 regions with moderate (basal forebrain), minimal (superior frontal cortex) and no Lewy body pathology (superior occipital cortex) from individuals without PD (n=10) and PD patients (n=10) with both technologies. We assessed differential expression and alternative splicing (AS) of genes as well as gene co-expression networks. We found compensatory mechanisms in the pathologically unaffected regions, including upregulation of genes HSPA6 (log₂FC=4.5 SOC, log₂FC=4.1 SFC, molecular chaperone) and VAMP2 (log₂FC=7.63 SOC:BF). Splicing events were dramatically dysregulated, including mis-splicing of many PD familial and GWAS associated genes. Importantly these genes were not altered by differential expression at the gene level, highlighting complex dysregulation of the PD transcriptome. We used a combination of publicly available data to predict which regulatory splicing factors are driving the splicing dysregulation in PD. We show the addition of α-synuclein pre-formed fibrils to mouse primary hippocampal neurons is sufficient to cause mis-localisation of the predicted RNA binding proteins and that splicing factors are dysregulated in PD patient brains prior to pathology. Alternative splicing dysregulation in PD is substantially underappreciated and the identification of a program of regulatory splicing factors affected by α-synuclein could offer novel insights and treatment avenues for PD.