Protein Kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer to two catalytic (C) subunits. Recently, the L50R variant in the gene encoding the RIβ subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIβ-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined postmortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry, and behavioral assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIβ is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer’s mouse models with age, while aggregation is accelerated in the RIβ-L50R mouse model. We define RIβ-L50R as a causal mutation driving an age-dependent behavioral and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIβ dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the C-subunit protects the RIβ-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIβ-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases.

中文翻译：

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PRKAR1B 基因突变驱动跨物种神经退行性病变的病理机制

蛋白激酶 A (PKA) 神经元功能由调节 (R) 亚基二聚体与两个催化 (C) 亚基的相互作用控制。最近，在患有新型神经退行性疾病的个体中发现了编码 RIβ 亚基的基因中的 L50R 变异。然而，驱动疾病表型的机制仍然未知。在这项研究中，我们构建了携带 RIβ-L50R 突变的小鼠模型，以复制人类疾病表型并研究其随年龄的进展。我们检查了受影响个体的死后大脑以及活细胞培养物。通过生化检测、免疫组织化学和行为评估，我们研究了突变对 PKA 复合物组装、蛋白质聚集和神经元变性的影响。我们发现，RIβ 是一种易于聚集的蛋白质，在野生型和阿尔茨海默病小鼠模型中随着年龄的增长逐渐积累，而在 RIβ-L50R 小鼠模型中聚集加速。我们将 RIβ-L50R 定义为在人类和小鼠模型中驱动年龄依赖性行为和疾病表型的因果突变。从机制上讲，这种突变破坏了 RIβ 二聚化，导致其单体聚集。有趣的是，与 C 亚基的相互作用以剂量依赖性方式保护 RIβ-L50R 免于自我聚集。此外，cAMP 信号传导诱导 RIβ-L50R 聚集。本文阐明了一种新认识的神经退行性疾病的病理生理学机制，其中蛋白质聚集是同二聚化破坏的结果，揭示了几种神经退行性疾病中一种明显未被充分认识但可能常见的机制。