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Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches

Eliona Tsefou, Alison S. Walker, Emily H. Clark, Amy R. Hicks, Christin Luft, Kunitoshi Takeda, Toru Watanabe, Bianca Ramazio, James M. Staddon, Thomas Briston, Robin Ketteler
doi: https://doi.org/10.1101/2021.02.02.429344
Eliona Tsefou
1MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
2UCL:Eisai Therapeutic Innovation Group, Translational Research Office, University College London, London, United Kingdom
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Alison S. Walker
3Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, United Kingdom
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Emily H. Clark
3Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, United Kingdom
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Amy R. Hicks
3Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, United Kingdom
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Christin Luft
1MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
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Kunitoshi Takeda
3Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, United Kingdom
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Toru Watanabe
3Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, United Kingdom
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Bianca Ramazio
3Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, United Kingdom
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James M. Staddon
3Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, United Kingdom
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Thomas Briston
3Neurology Innovation Centre, Hatfield Research Laboratories, Eisai Ltd., Hatfield, United Kingdom
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  • For correspondence: Thomas_briston@eisai.net r.ketteler@ucl.ac.uk
Robin Ketteler
1MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
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  • For correspondence: Thomas_briston@eisai.net r.ketteler@ucl.ac.uk
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Summary

Mitochondrial dysfunction is implicated in Parkinson disease (PD). Mutations in Parkin, an E3 ubiquitin ligase, can cause juvenile-onset Parkinsonism probably through impairment of mitophagy. Inhibition of the de-ubiquitinating enzyme USP30 may counter this effect to enhance mitophagy. Using different tools and cellular approaches, we wanted to independently confirm this claimed role for USP30. Pharmacological characterization of additional tool compounds that selectively inhibit USP30 are reported. The consequence of USP30 inhibition by these compounds, siRNA knockdown and overexpression of dominant-negative USP30 in the mitophagy pathway in different disease-relevant cellular models was explored. Knockdown and inhibition of USP30 showed increased p-Ser65-ubiquitin levels and mitophagy in neuronal cell models. Furthermore, patient-derived fibroblasts carrying pathogenic mutations in Parkin showed reduced p-Ser65-ubiquitin levels compared to wild-type cells, levels that could be restored using either USP30 inhibitor or dominant-negative USP30 expression. Our data provide additional support for USP30 inhibition as a regulator of the mitophagy pathway.

Competing Interest Statement

E.C, K.T, T.W, J.S and TB are current employees of Eisai. A.W, A.H, B.R were past employees of Eisai.

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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 February 02, 2021.
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Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches
Eliona Tsefou, Alison S. Walker, Emily H. Clark, Amy R. Hicks, Christin Luft, Kunitoshi Takeda, Toru Watanabe, Bianca Ramazio, James M. Staddon, Thomas Briston, Robin Ketteler
bioRxiv 2021.02.02.429344; doi: https://doi.org/10.1101/2021.02.02.429344
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Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches
Eliona Tsefou, Alison S. Walker, Emily H. Clark, Amy R. Hicks, Christin Luft, Kunitoshi Takeda, Toru Watanabe, Bianca Ramazio, James M. Staddon, Thomas Briston, Robin Ketteler
bioRxiv 2021.02.02.429344; doi: https://doi.org/10.1101/2021.02.02.429344

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