The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo

Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson’s disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2(G2019S)) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) “cell-autonomous”. Here, we explored whether ΔLRRK2(G2019S) could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2(G2019S) or its “dead” kinase form, ΔLRRK2(DK), and human α-syn with the A53T mutation (AAV-α-syn(A53T)). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-syn(A53T) alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-syn(A53T) with AAV-ΔLRRK2(G2019S) induced DA neuron degeneration that was significantly higher than that induced by AAV-α-syn(A53T) alone or with AAV-ΔLRRK2(DK). Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2(G2019) alone(,) through cell-autonomous mechanisms.