LRRK2 G2019S Missense Mutation Increases PKA Activity in a Preliminary Investigation
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Mutations in leucine-rich repeat kinase 2 genes (LRRK2) are the most common genetic causes of Parkinson's disease (PD); they are also associated with some sporadic cases of PD. Despite the relevance ofLRRK2 in PD, its cellular function is not well characterized. Previous studies have shown that LRRK2 interacts with the regulatory PKARIIp subunit and directs neuronal PKA signaling. The second most common mutation ofLRRK2 in PD, the R1441C mutation, is known to impair this interaction, resulting in an increase in PKA signaling. Considering the R1441C mutation, we aimed to understand the most common genetic mutation in PD patients, the G2019S missense mutation, which lies in the kinase domain ofLRRK2, and its effects on PKA signaling in Ml7 cells and primary striatal neurons. Cell lines were transfected with the G2019S mutated LRRK2 gene, while primary striatal neurons were extracted from wild-type, R1441C, and G2019S transgenic mice. Western blot analysis was used to compare phosphorylated PKA substrates detected in the two model systems after PKA and dopaminergic signaling manipulation. We confirmed that the R1441C mutation increases PKA signaling in primary striatal neurons. We also demonstrated that the G2019S mutation increases PKA signaling in Ml7 cells and primary striatal neurons. This implies that different pathogenic mutations ofLRRK2 may affect the same signaling pathways in PD. These findings also suggest that the impairment of the interaction between LRRK2 and PKA may account for precursors to striatum dysfunction, contributing to motor symptoms of PD. Understanding the mechanistic roles ofLRRK2 mutations could further provide insight into therapeutic targets for the treatment of PD as well.