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

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.

N‐Cyanopiperazines as Specific Covalent Inhibitors of the Deubiquitinating Enzyme UCHL1

“…In contrast, the cyanopiperazine only inhibited UCHL1 to a similar degree. Considering the high concentration of the compound, the large size of the panel of DUBs and the high propensity of many of these to react with electrophilic fragments, this specificity is striking also in the context of previously recorded profiles [8,10,19,41] …”

“…The relevance of nitrile‐based DUB inhibitors is illustrated by the successful completion of the first clinical trial of a cyanopyrrolidine on USP30 in 2023, demonstrating the translational potential of both this substance class and of deubiquitinating enzymes as therapeutic targets [12,16] . Moreover, bicyclic cyanamides [19,20] with nanomolar potencies on USP30 were reported, of which compound MTX115325 protected dopaminergic neurons in a Parkinson's disease mouse model [19] . In addition, nitriles have been reported as covalent inhibitors of Cathepsins, [21] of dipeptidyl peptidase 4 in anti‐diabetic drugs, [22] and of the main protease of SARS‐CoV‐2 in the drug paxlovid [23]…”

Discovery of potent and selective activity-based probes (ABPs) for the deubiquitinating enzyme USP30

“…Dysregulation of USP30 is implicated in a range of rare genetic mitochondrial diseases, and neurodegenerative diseases including Parkinson's disease. 12 Accordingly, there is significant interest in developing USP30 inhibitors for the clinic, and Mission Therapeutics initiated the first clinical trials of a USP30 inhibitor in 2022 for muscular, cardiac and kidney pathologies, 34 reporting encouraging Phase I safety data. Selective and potent small molecule USP30 ABPs would be useful tools to explore the role of USP30 activity in intact cells for these diseases.…”

“…9 Overexpression of USP30 and dysregulation in mitochondrial turnover has been associated with neurodegenerative diseases including Parkinson's disease, Alzheimer's disease and motor neuron disease. 10–12 USP30 may also play a role in drug resistant lymphoma, leukaemia, multiple myeloma, and BAX/BAK-dependent apoptosis. 3 USP30 depletion sensitizes cancer cells to BH3-mimetics ( e.g.…”

Ellagic Acid Prevents α-Synuclein Spread and Mitigates Toxicity by Enhancing Autophagic Flux in an Animal Model of Parkinson’s Disease

“…A very recent article has showed that knockout of UPS30 or the selective inhibitor of UPS30 is beneficial as a disease-modifying target that enhances the clearance of defective mitochondria induced by aggregated synuclein [ 64 ]. It has been suggested that the suppression of USP30 may have a significant impact on mitochondrial morphology, maintenance and function, and thus, risk associated with its suppression should be noted carefully.…”