The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo
In: International Journal of Molecular Sciences International Journal of Molecular Sciences, 2021, 22 (13), pp.6760. ⟨10.3390/ijms22136760⟩ Volume 22 Issue 13, Jg. 22 (2021), Heft 6760, p 6760
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Zugriff:
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 (ΔLRRK2G2019S) 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 ΔLRRK2G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2G2019S or its “dead” kinase form, ΔLRRK2DK, and human α-syn with the A53T mutation (AAV-α-synA53T). 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-synA53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-synA53T with AAV-ΔLRRK2G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-synA53T alone or with AAV-ΔLRRK2DK. Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2G2019 alone, through cell-autonomous mechanisms.
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The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo
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Autor/in / Beteiligte Person: | Bernier, Sueva ; Bemelmans, Alexis-Pierre ; Dufour, Noelle ; Bonvento, Gilles ; Gaillard, Marie-Claude ; Liot, Géraldine ; Gipchtein, Pauline ; Cresto, Noémie ; Gardier, Camille ; Hantraye, Philippe ; Auregan, Gwenaëlle ; Nadja Van Camp ; Molina, Daniela ; Jan, Caroline ; Guillermier, Martine ; Chartier-Harlin, Marie-Christine ; Gubinelli, Francesco ; Taymans, Jean-Marc ; Roost, Pauline ; Joséphine, Charlène ; Cambon, Karine ; Brouillet, Emmanuel ; Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN) ; Service MIRCEN (MIRCEN) ; Université Paris-Saclay-Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) ; Lille Neurosciences & Cognition - U 1172 (LilNCog) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille) ; Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Université Paris-Saclay, CEA, CNRS, Laboratoire des Maladies Neurodégénératives, MIRCen, F-92265 Fontenay-aux-Roses, France ; Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) ; Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)) |
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Zeitschrift: | International Journal of Molecular Sciences International Journal of Molecular Sciences, 2021, 22 (13), pp.6760. ⟨10.3390/ijms22136760⟩ Volume 22 Issue 13, Jg. 22 (2021), Heft 6760, p 6760 |
Veröffentlichung: | HAL CCSD, 2021 |
Medientyp: | unknown |
ISSN: | 1661-6596 (print) ; 1422-0067 (print) |
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