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-RIIbeta subunit level in the SNc of PD patients. The decreased PKA-RIIbeta subunit level was positively correlated with decreased dopamine synthesis and increased oxidative stress in the SNc of PD patients. PKA-RIIbeta subunit is expressed in the striatum and the SNc. PKA-RIIbeta gene knockout mice (RIIbeta-KO) showed a age-related parkinsonism at 12 months of age. Using Cre-LoxP system, we observed that RIIbeta; re-expression in the SNc dopaminergic neurons rescued parkinsonism of RIIbeta-KO mice. RIIbeta re-expression in striatal neurons did not affect parkinsonism of RIIbeta-KO mice. The spontaneous parkinsonism could be developed in 12-month-old SNc dopaminergic neuron-specific RIIbeta-deficient mice. Single-nucleus RNA sequencing revealed decreased PKA activity, reduced dopamine synthesis and raised oxidative stress in the SNc dopaminergic neurons of RIIbeta-KO mice. Adeno-associated virus (AAV)-mediated gene therapy targeting PKA-RIIbeta in the SNc dopaminergic neurons rescued parkinsonism in PD mouse model. Taken together, these findings indicate that PKA-RIIbeta may be a key factor of human genetic etiologies of PD. The therapy targeting PKA-RIIbeta in the SNc dopaminergic neurons may be promising for PD treatment.