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

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Parkinson's disease (PD) is a prevalent neurodegenerative disorder.
• Mild cognitive impairment (MCI) is a significant risk factor for dementia in PD patients.
• Reduced glucocerebrosidase (GBA) expression is implicated in PD progression and alpha-synuclein (α-Syn) aggregation.

Purpose of the Study:

• To identify genetic markers associated with PD and MCI.
• To elucidate the role of GBA gene expression in PD pathogenesis.
• To investigate the functional impact of a specific GBA eQTL (rs12411216) on PD-MCI.

Main Methods:

• Analysis of genomic data (DHS, eQTL SNP, transcription factor binding sites) to locate GBA eQTLs.
• Genotyping of 306 PD patients to assess the association of rs12411216 with PD-MCI.
• Quantitative PCR (qPCR) to verify the association between rs12411216 and GBA expression.
• CRISPR/Cas9 genome editing and electrophoretic mobility shift assays (EMSA) to study the functional effects of rs12411216 on GBA expression, enzymatic activity, α-Syn aggregation, and transcription factor binding.

Main Results:

• The GBA eQTL rs12411216 was identified and found to be significantly associated with PD-MCI.
• rs12411216 is directly correlated with reduced GBA expression and weakened GBA enzymatic activity.
• This SNP enhances abnormal α-Syn aggregation and affects transcription factor E2F4 binding efficiency.
• Experimental models confirmed that rs12411216 leads to decreased GBA expression and increased α-Syn aggregation.

Conclusions:

• The genetic variant rs12411216 regulates GBA expression, impacting PD pathogenesis.
• rs12411216 shows potential as a genetic biomarker for PD with MCI.
• These findings reveal novel molecular mechanisms contributing to Parkinson's disease progression.