The C-terminal domain of LRRK2 with the G2019S mutation is sufficient to produce neurodegeneration of dopaminergic neurons in vivo

Cresto, Noémie; Gaillard, Marie-Claude; Gardier, Camille; Gubinelli, Francesco; Diguet, Elsa; Bellet, Déborah; Legroux, Laurine; Mitja, Julien; Aurégan, Gwenaëlle; Guillermier, Martine; Joséphine, Charlène; Jan, Caroline; Dufour, Noëlle; Joliot, Alain; Hantraye, Philippe; Bonvento, Gilles; Déglon, Nicole; Bemelmans, Alexis-Pierre; Cambon, Karine; Liot, Géraldine; Brouillet, Emmanuel

doi:10.1016/j.nbd.2019.104614

Cited by 20 publications

(24 citation statements)

References 54 publications

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“…Neuropathological evaluation at 15 weeks PI after transduction with AAV-α-syn A53T showed the partial loss of DA neurons, based on the detection of TH-positive cells. This likely reflects neuronal loss, as suggested in our previous work [29].…”

Section: Discussionsupporting

confidence: 69%

“…There is limited evidence obtained in vivo that shows a relationship between the higher kinase activity of LRRK2 G2019S and neurotoxicity to dopaminergic cells of the SNc. The overexpression of LRRK2 G2019S (or ΔLRRK2 G2019S ) in the SNc was found to induce the loss of DA neurons using HSV and adenovirus models injected into the striatum [23,55], as well as in our previous study with AAV-ΔLRRK2 G2019S injected into the SNc [56].…”

Section: Discussionmentioning

confidence: 64%

“…Indeed, ΔLRRK2 G2019S lacks N-terminal domains that are known to play crucial roles in LRRK2 function. we previously showed that overexpression of the ΔLRRK2 G2019S fragment using AAVs triggers neurodegeneration of DA neurons six months post-transduction, whereas the ΔLRRK2 WT fragment, expressed at similar high levels, was devoid of obvious neurotoxicity [29]. Cell death produced by this fragment which has a detectable kinase activity is likely independent of the interaction with RAB10, since the ΔLRRK2 fragment was found unable to interact with RAB10, in contrary to full-length LRRK2 fragment [29].…”

Section: Discussionmentioning

confidence: 95%

“…we previously showed that overexpression of the ΔLRRK2 G2019S fragment using AAVs triggers neurodegeneration of DA neurons six months post-transduction, whereas the ΔLRRK2 WT fragment, expressed at similar high levels, was devoid of obvious neurotoxicity [29]. Cell death produced by this fragment which has a detectable kinase activity is likely independent of the interaction with RAB10, since the ΔLRRK2 fragment was found unable to interact with RAB10, in contrary to full-length LRRK2 fragment [29]. Thus, it is conceivable that the overexpression of ΔLRRK2 G2019S leads to abnormal/higher phosphorylation of substrates, relative to that by the overexpression of ΔLRRK2 WT , that is at least partially in common with that of full-length LRRK2 [40][41][42][43].…”

Section: Discussionmentioning

confidence: 97%

“…We used AAVs, which allow selective expression in neuronal cells and efficiently transduce a large volume of brain tissue due to their good diffusion properties. In a previous study [29], we showed that the C-terminal portion of human LRRK2 G2019S (ΔLRRK2 G2019S , 1330-2527 aa) retains, at least in part, the biochemical properties of full-length LRRK2 G2019S , including higher kinase activity than the wildtype fragment. In addition, we found that overexpression of the C-terminal portion of human ΔLRRK2 G2019S in the adult rat SNc, using AAVs, produced partial (~ 30%) but significant loss of DA neurons at 25 weeks post-transduction, whereas overexpression of the wildtype form of LRRK2 (ΔLRRK2 WT ) was not toxic.…”

Section: G2019s Toxicitymentioning

confidence: 99%

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The C-terminal fragment of LRRK2 with the G2019S substitution increases the neurotoxicity of mutant A53T α-synuclein in dopaminergic neurons in vivo

Cresto

Gardier

Gaillard

et al. 2020

Preprint

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Background: Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) likely play crucial roles both in sporadic and familial forms of Parkinson’s disease (PD). The most prevalent mutation in LRRK2 is the G2019S substitution, which induces neurotoxicity through increased kinase activity. There is likely an interplay between LRRK2 and α-syn involved in the neurodegeneration of dopaminergic (DA) neurons in the substantia nigra (SNc) in PD. However, the mechanisms underlying this interplay are ill-defined. Here, we investigated whether LRRK2G2019S can increase the neurotoxicity induced by a mutant form of α-syn (A53T mutation) in DA neuronsin vivo.Methods: We used a co-transduction approach with AAV2/6 vectors encoding human a-synA53T and the C-terminal portion of LRRK2 (ΔLRRK2), which contains the kinase domain, with either the G2019S mutation (ΔLRRK2G2019) alone or the D1994A mutation (ΔLRRK2G2019S/D1994A), which inactivates the kinase activity of LRRK2. The AAVs were co-injected into the rat SNc and histological evaluation was performed at 6- and 15-weeks post-injection (PI). Results: Most SNc neurons co-expressed ΔLRRK2 and human α-synA53T after transduction. ΔLRRK2G2019S alone produced no cell loss at 15-weeks PI, whereas as expected, transduction with AAV-a-synA53T mixed with a control AAV coding for GFP produced significant loss of DA neurons. Co-injection of AAV-ΔLRRK2G2019S and AAV-α-synA53T induced a loss of DA neurons slightly but significantly greater than that produced by co-injection of AAV-α-synA53T and AAV-GFP. We also studied the inactive form, ΔLRRK2G2019S/D1994A at 6 weeks PI. Results showed that ΔLRRK2G2019S/D1994A did not alter the early toxicity of α-synA53T, in contrast to the active form ΔLRRK2G2019S that produced a moderate but significant increase in α-synA53T toxicity.Conclusion. Thus, these results show that mutant LRRK2 may selectively facilitate α-syn toxicity in DA neurons through a cell-autonomous mechanism involving its kinase activity. However, considering that the effect of ΔLRRK2G2019S upon human α-synA53T is moderate in our paradigm where pathological proteins are overexpressed, the study supports the hypothesis that the interplay between LRRK2 and α-syn also implicates non-cell-autonomous mechanisms such as those involved in neuroinflammation.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 97%

Section: G2019s Toxicitymentioning

confidence: 99%

See 3 more Smart Citations

The C-terminal fragment of LRRK2 with the G2019S substitution increases the neurotoxicity of mutant A53T α-synuclein in dopaminergic neurons in vivo

Cresto

Gardier

Gaillard

et al. 2020

Preprint

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Translational View on Therapeutic Strategies and Upcoming Issues: Stem Cell and Brain Organoid Approaches for Parkinson’s Disease Therapy

Gubinelli,

Salazar,

Kaspar

et al. 2024

Neuromethods

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Multi-method computational evaluation of the inhibitors against leucine-rich repeat kinase 2 G2019S mutant for Parkinson's disease

Elhadi,

Zhao,

Ali

et al. 2024

Mol Divers

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Leucine-rich repeat kinase 2 G2019S mutant (LRRK2 G2019S) is a potential target for Parkinson's disease therapy. In this work, the computational evaluation of the LRRK2 G2019S inhibitors was conducted via a combined approach which contains a preliminary screening of a large database of compounds via similarity and pharmacophore, a secondary selection via structure-based a nity prediction and molecular docking, and a rescoring treatment for the nal selection. MD simulations and MM/GBSA calculations were performed to check the agreement between different prediction methods for these inhibitors. 331 experimental ligands were collected, and 170 were used to build the structure-activity relationship. Eight representative ligand structural models were employed in similarity searching and pharmacophore screening over fourteen million compounds. The process for selecting proper molecular descriptors provides a successful sample which can be used as a general strategy in QSAR modelling. The rescoring used in this work presents an alternative useful treatment for ranking and selection.

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The C-terminal domain of LRRK2 with the G2019S mutation is sufficient to produce neurodegeneration of dopaminergic neurons in vivo

Cited by 20 publications

References 54 publications

The C-terminal fragment of LRRK2 with the G2019S substitution increases the neurotoxicity of mutant A53T α-synuclein in dopaminergic neurons in vivo

The C-terminal fragment of LRRK2 with the G2019S substitution increases the neurotoxicity of mutant A53T α-synuclein in dopaminergic neurons in vivo

Translational View on Therapeutic Strategies and Upcoming Issues: Stem Cell and Brain Organoid Approaches for Parkinson’s Disease Therapy

Multi-method computational evaluation of the inhibitors against leucine-rich repeat kinase 2 G2019S mutant for Parkinson's disease

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