Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model

Tracy-Shi Zhang Fang (), Yu Sun, Andrew C. Pearce, Simona Eleuteri, Mark Kemp, Christopher A. Luckhurst, Rachel Williams, Ross Mills, Sarah Almond, Laura Burzynski, Nóra M. Márkus, Christopher J. Lelliott, Natasha A. Karp, David J. Adams, Stephen P. Jackson, Jin-Feng Zhao, Ian G. Ganley, Paul W. Thompson (), Gabriel Balmus () and David K. Simon
Additional contact information
Tracy-Shi Zhang Fang: Beth Israel Deaconess Medical Center and Harvard Medical School
Yu Sun: University of Cambridge, Cambridge Biomedical Campus
Andrew C. Pearce: Babraham Research Campus
Simona Eleuteri: Beth Israel Deaconess Medical Center and Harvard Medical School
Mark Kemp: Babraham Research Campus
Christopher A. Luckhurst: Babraham Research Campus
Rachel Williams: Babraham Research Campus
Ross Mills: Babraham Research Campus
Sarah Almond: Babraham Research Campus
Laura Burzynski: Babraham Research Campus
Nóra M. Márkus: Babraham Research Campus
Christopher J. Lelliott: Wellcome Sanger Institute
Natasha A. Karp: Wellcome Sanger Institute
David J. Adams: Wellcome Sanger Institute
Stephen P. Jackson: Babraham Research Campus
Jin-Feng Zhao: University of Dundee
Ian G. Ganley: University of Dundee
Paul W. Thompson: Babraham Research Campus
Gabriel Balmus: University of Cambridge, Cambridge Biomedical Campus
David K. Simon: Beth Israel Deaconess Medical Center and Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson’s disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria (“mitophagy”) by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.

Date: 2023
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DOI: 10.1038/s41467-023-42876-1

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