Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function

Area of Science:

• Cardiology
• Neuroscience
• Genetics

Background:

• Cardiomyopathy is a known comorbidity in some prion diseases, particularly those with genetic mutations in the prion protein gene (PRNP).
• The role of cellular prion protein (PrP) in cardiac function and its link to cardiomyopathy in prion diseases remains unclear.
• While PrP can protect against oxidative stress-induced cardiotoxicity, its direct involvement in disease-related cardiomyopathy needs elucidation.

Purpose of the Study:

• To investigate the direct impact of the PRNP E200K mutation on cardiomyocyte function.
• To determine if PRNP dysfunction is a direct cause of cardiomyopathy in hereditary prion diseases.
• To analyze the effects of the E200K mutation on cellular electrophysiology and mitochondrial activity in cardiomyocytes.

Main Methods:

• Differentiated human induced pluripotent stem cell-derived cardiomyocyte cultures.
• Utilized CRISPR-Cas9 gene editing to correct the E200K mutation in carrier cells and introduce it into control cells.
• Assessed cardiomyocyte function, electrophysiology, mitochondrial membrane potential, and superoxide levels.

Main Results:

• PRNP E200K cardiomyocytes exhibited abnormal function, specifically irregular rapid repolarization, similar to Down Syndrome cardiomyocytes.
• Elevated mitochondrial superoxide and increased mitochondrial membrane potential were observed in PRNP E200K cardiomyocytes, indicating mitochondrial dysfunction.
• CRISPR-Cas9 gene editing confirmed that the lysine-expressing allele (E200K) directly influences cardiomyocyte electrophysiology and mitochondrial function, though severity varied by donor line.

Conclusions:

• The E200K mutation in the prion protein gene directly impairs cardiomyocyte function and mitochondrial health.
• This study provides direct evidence linking PrP dysfunction to cardiomyopathy in hereditary prion diseases.
• Findings suggest that targeting PrP function could be a therapeutic strategy for prion disease-associated cardiomyopathy.