Characterization of a pathogenic variant in GBA for Parkinson's disease with mild cognitive impairment patients

Parkinson's disease (PD) is the second most common neurodegenerative disease, and mild cognitive impairment (MCI) is a well-established risk factor for the development of dementia in PD. A growing body of evidence suggests that low expression of glucocerebrosidase (GBA) promotes the transmission of alpha-synuclein (alpha-Syn) interpolymers and the progression of PD. However, howGBAmutations affect the pathogenesis of PD via abnormal aggregation of alpha-Syn is unclear, and no clinically valid PD-MCI genetic markers have been identified. Here, we first located aGBAeQTL, rs12411216, by analysing DHS, eQTL SNP, and transcription factor binding site data using the UCSC database. Subsequently, we found that rs12411216 was significantly associated with PD-MCI (P < 0.05) in 306 PD patients by genotyping. In exploring the relationship between rs12411216 andGBAexpression, the SNP was found to be associated withGBAexpression in 50 PD patients through qPCR verification. In a further CRISPR/Cas9-mediated genome editing module, the SNP was identified to cause a decrease inGBAexpression, weaken enzymatic activity and enhance the abnormal aggregation of alpha-Syn in SH-SY5Y cells. Additionally, using an electrophoretic mobility shift assay, we confirmed that the binding efficiency of transcription factor E2F4 was affected by the rs12411216 SNP. In conclusion, our results showed that rs12411216 regulated GBA expression, supporting its potential role as a PD-MCI genetic biomarker and highlighting novel mechanisms underlying Parkinson's disease.