Gene expression asymmetry in Parkinson’s disease: variation of CCT gene expression is correlated with hemisphere specific severity

Parkinson's disease (PD) symptom onset is typically unilateral, which may be related to molecular differences underlying hemispheric vulnerability. Here we sampled prefrontal cortex bilaterally from people with PD and healthy controls and performed RNA-seq on neuronal nuclei to determine hemispheric and disease-related differences. Brain hemispheres were categorized based on whether they corresponded to the side of symptom onset (severe) or the opposite side (moderate) and compared for differences in gene expression. We employed two <i>a priori</i> approaches; first we identified genes differentially expressed between PD and controls and between PD brain hemispheres. Second, we examined the presence of, and correlates to, variations in the asymmetry for some differentially expressed genes. We found large variation among individuals with PD, and so PD stratification by gene expression signature was required for patterns of genetic asymmetry to emerge. For a subset of PD brains, hemispherical variation of <i>CCT</i> gene levels correlated with the side of PD symptom onset. In a mouse model of PD, neurons with <i>α</i>-synuclein inclusions had decreased <i>Cct</i> expression. These results suggest that <i>CCT</i> expression plays a protective role in PD.