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

Abstract 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. Each brain hemisphere was related the side of symptom onset and compared. We employed two a priori 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, variable asymmetry seen in candidate PD 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 CCT gene levels correlated with the side of PD symptom onset. In a mouse model of PD, neurons with α-synuclein inclusions had decreased Cct expression. These results suggest that CCT expression plays a protective role in PD.