Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis

Area of Science:

• Neurogenetics
• Molecular Biology
• Biochemistry

Background:

• Parkinson's disease (PD) is often sporadic but has a significant genetic component.
• Investigating genetic factors is crucial for understanding PD etiology.

Purpose of the Study:

• Identify the genetic cause of PD in two affected siblings.
• Evaluate the role of Cathepsin B (CTSB) mutations in PD susceptibility.

Main Methods:

• Whole-exome sequencing in affected siblings.
• Sanger sequencing for variant validation.
• Genotyping of CTSB p.Gly284Val in large PD cohorts and controls.
• Gene burden analysis in familial PD cohorts.
• Assessment of CTSB expression and activity in patient-derived fibroblasts.

Main Results:

• The CTSB p.Gly284Val variant was exclusively found in affected family members.
• Functional studies in fibroblasts showed no significant changes in CTSB expression, localization, or activity in heterozygous carriers.
• No significant association was found between CTSB variants and PD risk in the studied cohorts.

Conclusions:

• The CTSB p.Gly284Val variant may contribute to PD risk, potentially with incomplete penetrance.
• Further research is needed to elucidate the precise role of CTSB in PD pathogenesis.