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Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model
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Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model
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Journal Article
Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model
2023
Overview
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.
USP30 has been proposed to regulate mitophagy, a relevant Parkinson’s disease mechanism. Here, the authors show that
Usp30
knockout mice and USP30 inhibitors like MTX115325 demonstrate neuroprotective responses in an alpha-synuclein mouse model of Parkinson’s disease.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/77
/ 42/44
/ 631/154
/ 64/60
/ 82/51
/ alpha-Synuclein - metabolism
/ Animals
/ Dopaminergic Neurons - metabolism
/ Humanities and Social Sciences
/ Mice
/ Mutation
/ Neurons
/ Parkinson Disease - metabolism
/ Proteins
/ PTEN-induced putative kinase
/ Science
/ Thiolester Hydrolases - genetics
/ Toxicity
/ Ubiquitin-Protein Ligases - genetics
