Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers

Area of Science:

• Genetics
• Neuroscience
• Mitochondrial Biology

Background:

• Pathogenic biallelic variants in the PRKN gene cause Parkinson's disease (PD).
• Heterozygous PRKN variants are common and may increase PD risk with reduced penetrance via mitochondrial dysfunction.
• Identifying presymptomatic markers in heterozygous carriers is crucial for early intervention.

Purpose of the Study:

• To investigate mitochondrial function in cells from non-manifesting heterozygous PRKN variant carriers.
• To identify potential presymptomatic molecular markers for PD risk in these individuals.
• To assess the utility of these markers for monitoring disease progression and testing therapies.

Main Methods:

• Generation of lymphoblasts (LCLs) and human induced pluripotent stem cell (hiPSC)-derived neurons from heterozygous PRKN variant carriers.
• Assessment of mitochondrial functionality, including respiration, in derived cell types.
• Comparison of cellular phenotypes between carriers, non-carriers, and a biallelic PRKN-PD patient.

Main Results:

• LCLs from carriers exhibited hyperactive mitochondrial respiration.
• hiPSC-derived neurons from carriers showed altered mitochondrial function, though milder than in biallelic PD patients.
• Identified specific molecular phenotypes indicative of mitochondrial dysfunction in heterozygous carriers.

Conclusions:

• Molecular phenotypes associated with mitochondrial dysfunction can be detected in non-manifesting heterozygous PRKN variant carriers.
• These phenotypes may serve as presymptomatic markers for monitoring carriers and assessing neuroprotective therapies.
• Further research can leverage these markers to predict PD risk and guide early therapeutic strategies.