Age-related decline of PKA-RIIβ level in SNc dopaminergic neurons underlies PD pathogenesis

The cyclic-AMP dependent protein kinase A (Protein kinase A, PKA) regulates dopaminergic function in the substantia nigra pars compacta (SNc). However, whether PKA is involved in the pathogenesis of Parkinson’s disease (PD) is unknown. Here, by collecting and analyzing the current worldwide SNc transcriptomic datasets of PD patients, we found a decline of PKA-RIIβ subunit level in the SNc of PD patients. The decreased PKA-RIIβ subunit level was positively correlated with decreased dopamine synthesis and increased oxidative stress in the SNc of PD patients. PKA-RIIβ subunit is expressed in the striatum and the SNc. PKA-RIIβ gene knockout mice (RIIβ-KO) showed a age-related parkinsonism at 12 months of age. Using Cre-LoxP system, we observed that RIIβ re-expression in the SNc dopaminergic neurons rescued parkinsonism of RΙΙβ-KO mice. RIIβ re-expression in striatal neurons did not affect parkinsonism of RΙΙβ-KO mice. The spontaneous parkinsonism could be developed in 12-month-old SNc dopaminergic neuron-specific RIIβ-deficient mice. Single-nucleus RNA sequencing revealed decreased PKA activity, reduced dopamine synthesis and raised oxidative stress in the SNc dopaminergic neurons of RIIβ-KO mice. Adeno-associated virus (AAV)-mediated gene therapy targeting PKA-RΙΙβ in the SNc dopaminergic neurons rescued parkinsonism in PD mouse model. Taken together, these findings indicate that PKA-RIIβ may be a key factor of human genetic etiologies of PD. The therapy targeting PKA-RIIβ in the SNc dopaminergic neurons may be promising for PD treatment.