PKA missense mutation drives structural defects and protein misfolding in patiants with a rare neurodegenerative disease

Dysregulation of cAMP signaling contributes to the etiology of several brain degenerative diseases. A missense mutation in PKA RIb regulatory subunit, the least studied isoform, was found in patients diagnosed with a rare neurodegenerative disease. The gap in knowledge regarding this gene and the devastating outcomes seen in individuals with motor deficits are two critically important problems that we are currently researching. Our recent structural model led us to hypothesize that an amino acid substitution L50R may result in preventing dimer formation. Biochemical studies as well as cell-based high-resolution image analysis suggest that this RIb missense mutation not only prevents RIb homodimerization but also eliminates the binding site that is created by dimer formation for A Kinase Anchoring Proteins (AKAPs) binding. Consequently, PKA holoenzyme localization is affected as evidenced by accumulation of RIb into neuronal inclusions in human brain patients. A quantitative multiplex proteomics revealed that the phospho-signaling cascade is disrupted by the L50R mutation in postmortem brains. This study emphasizes the importance of precisely controlled PKA isoform subcellular localization and demonstrates how a mutation in PKA regulatory subunit drives aberrant cAMP signaling and neurodegeneration. This study provides insights into the molecular and cellular mechanisms of other neurodegenerative diseases where PKA function is dysregulated.