Rare disease reveals potentially common mechanism

The protein cAMP-dependent protein kinase (PKA) complex contains a dimer of the regulatory subunit R, bound to two catalytic subunits. Recently, a specific leucine-to-arginine mutation of the regulatory subunit IRβ (RIβ-L50R) was detected in patients with a rare neurodegenerative disease characterized by dementia and/or parkinsonism. In an article published in the journal Brain, Dr. Ronit Ilouz, along with Dr. Ted Abel from Iowa Neuroscience Institute and Dr. Eduard Stefan from Erasmus University Medical Center, explore the mechanistic effect of this RIβ-L50R mutation on disease development. The researchers generated mice expressing the IRβ-L50R mutant protein, and found that while the wild-type protein is prone to aggregate in old age and cause neurodegenerative symptoms, the mutant PKA presents an accelerated aggregation. Mechanistically, the RIβ-L50R mutation prevents dimerization of the PKA subunits, which harms the protein's stability and enhances aggregation. This new mechanism of protein aggregation may potentially be common across several other neurodegenerative diseases.