SNP Identification And Functional Study Of GBA Regulatory Region Of Parkinson's Disease With Mild Cognitive Impairment

Parkinson's disease(Parkinson's disease,PD)has now become the second largest neurodegenerative disease after Alzheimer's disease.The motor symptoms of PD(bradykinesia,tremor,muscle stiffness,and abnormal posture and gait)are well known,but their non-motor symptoms are often overlooked;cognitive impairment is the most common and disabling nonmotor symptoms,including PD mild cognitive impairment(PD mild cognitive impairment,PDMCI)and PD dementia(PDD),MCI is one of the early warning signs of dementia in the late stage of PD.In recent years,more and more studies have shown that the loss of glucocerebrosidase GBA function mutation is associated with severe cognitive impairment in PD,and patients with GBA mutations in PD have a faster cognitive decline.Here,we first located a GBA e QTL rs12411216 by analyzing DHS,e QTL SNP,and transcription factor binding sites data in the UCSC database.And then we found that the rs12411216 was significantly associated with PD-MCI(P<0.05)in 306 PD patients by genotyping.To explore the relationship between rs12411216 and GBA expression,we found that the SNP was associated with GBA expression in 50 PD patients by q PCR,caused a decrease in GBA expression and enzymatic activity using CRISPR/Cas9-mediated genome editing,enhanced abnormal aggregation of pathology ?-Syn in SH-SY5 Y cells,affected the binding efficiency of the transcription factor E2F4 by electrophoretic mobility shift assay.In conclusion,our results suggest that rs12411216 regulates GBA expression,supporting its potential role as a PD-MCI genetic biomarker and highlights novel mechanisms underlying Parkinson diseases.