Résumé
Alpha-synuclein (alpha-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 (Delta LRRK2) with the G2019S mutation (Delta LRRK2(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 Delta LRRK2(G2019S) could modify alpha-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding Delta LRRK2(G2019S) or its "dead" kinase form, Delta LRRK2(DK), and human alpha-syn with the A53T mutation (AAV-alpha-syn(A53T)). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of Delta LRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-alpha-syn(A53T) alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-alpha-syn(A53T) with AAV-Delta LRRK2(G2019S) induced DA neuron degeneration that was significantly higher than that induced by AAV-alpha-syn(A53T) alone or with AAV-Delta LRRK2(DK). Thus, mutated alpha-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2(G2019) alone(,) through cell-autonomous mechanisms.