2. Academic Validation
  3. Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model

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

  • Nat Commun. 2023 Nov 13;14(1):7295. doi: 10.1038/s41467-023-42876-1.
Tracy-Shi Zhang Fang 1,  Yu Sun 2,  Andrew C Pearce 3,  Simona Eleuteri 4,  Mark Kemp 3,  Christopher A Luckhurst 3,  Rachel Williams 3,  Ross Mills 3,  Sarah Almond 3,  Laura Burzynski 3,  Nóra M Márkus 3,  Christopher J Lelliott 5,  Natasha A Karp 5,  David J Adams 5,  Stephen P Jackson 3 6 7,  Jin-Feng Zhao 8,  Ian G Ganley 8,  Paul W Thompson 9,  Gabriel Balmus 10 11,  David K Simon 4
Affiliations

Affiliations

  • 1 Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. szhang9@bidmc.harvard.edu.
  • 2 UK Dementia Research Institute at the University of Cambridge and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0AH, UK.
  • 3 Mission Therapeutics Ltd. Glenn Berge Building, Babraham Research Campus, Cambridge, CB22 3FH, UK.
  • 4 Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • 5 Wellcome Sanger Institute, Cambridge, CB10 1SA, UK.
  • 6 The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
  • 7 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0RE, UK.
  • 8 MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, DD1 5EH, UK.
  • 9 Mission Therapeutics Ltd. Glenn Berge Building, Babraham Research Campus, Cambridge, CB22 3FH, UK. PThompson@missiontherapeutics.com.
  • 10 UK Dementia Research Institute at the University of Cambridge and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0AH, UK. gb318@cam.ac.uk.
  • 11 Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, 400191, Cluj-Napoca, Romania. gb318@cam.ac.uk.
PMID: 37957154 DOI: 10.1038/s41467-023-42876-1
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.

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