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RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology

Julia Obergasteiger, Anne-Marie Castonguay, Giulia Frapporti, Evy Lobbestael, Veerle Baekelandt, Andrew A. Hicks, Peter P. Pramstaller, Claude Gravel, Corrado Corti, Martin Lévesque, View ORCID ProfileMattia Volta
doi: https://doi.org/10.1101/2020.10.21.348144
Julia Obergasteiger
1Institute for Biomedicine, Eurac Research, via Galvani 31, 39100, Bolzano (Italy)
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Anne-Marie Castonguay
2Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval; CERVO Brain Research Centre, 2601 chemin de la Canardiere, Quebec (QC, Canada)
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Giulia Frapporti
1Institute for Biomedicine, Eurac Research, via Galvani 31, 39100, Bolzano (Italy)
◻Department of Cellular, Computational and Integrative Biology-CIBO, University of Trento (Italy)
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Evy Lobbestael
3Department of Neurosciences, KU Leuven, Herestraat 49 bus 1023, 3000, Leuven, Belgium
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Veerle Baekelandt
3Department of Neurosciences, KU Leuven, Herestraat 49 bus 1023, 3000, Leuven, Belgium
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Andrew A. Hicks
1Institute for Biomedicine, Eurac Research, via Galvani 31, 39100, Bolzano (Italy)
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Peter P. Pramstaller
1Institute for Biomedicine, Eurac Research, via Galvani 31, 39100, Bolzano (Italy)
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Claude Gravel
2Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval; CERVO Brain Research Centre, 2601 chemin de la Canardiere, Quebec (QC, Canada)
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Corrado Corti
1Institute for Biomedicine, Eurac Research, via Galvani 31, 39100, Bolzano (Italy)
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Martin Lévesque
2Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval; CERVO Brain Research Centre, 2601 chemin de la Canardiere, Quebec (QC, Canada)
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  • For correspondence: martin.levesque@cervo.ulaval.ca mattia.volta@eurac.edu
Mattia Volta
1Institute for Biomedicine, Eurac Research, via Galvani 31, 39100, Bolzano (Italy)
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  • ORCID record for Mattia Volta
  • For correspondence: martin.levesque@cervo.ulaval.ca mattia.volta@eurac.edu
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Abstract

In Parkinson’s disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear but hypothesized to involve the autophagy lysosome pathways (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, hyperactivate kinase activity and its pharmacological inhibition reduces pS129-aSyn inclusions. We observed selective downregulation of the novel PD risk factor RIT2 in G2019S-LRRK2 expressing cells. Here we studied whether RIT2 could modulate LRRK2 kinase activity. RIT2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions. In vivo, viral mediated overexpression of RIT2 operated neuroprotection against AAV-A53T-aSyn. Furthermore, RIT2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo. Our data indicate that RIT2 inhibits overactive LRRK2 to ameliorate ALP impairment and counteract aSyn aggregation and related deficits. Targeting RIT2 could represent a novel strategy to combat neuropathology in familial and idiopathic PD.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 21, 2020.
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RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology
Julia Obergasteiger, Anne-Marie Castonguay, Giulia Frapporti, Evy Lobbestael, Veerle Baekelandt, Andrew A. Hicks, Peter P. Pramstaller, Claude Gravel, Corrado Corti, Martin Lévesque, Mattia Volta
bioRxiv 2020.10.21.348144; doi: https://doi.org/10.1101/2020.10.21.348144
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RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology
Julia Obergasteiger, Anne-Marie Castonguay, Giulia Frapporti, Evy Lobbestael, Veerle Baekelandt, Andrew A. Hicks, Peter P. Pramstaller, Claude Gravel, Corrado Corti, Martin Lévesque, Mattia Volta
bioRxiv 2020.10.21.348144; doi: https://doi.org/10.1101/2020.10.21.348144

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