inhibiting USP30 gene offers hope in treating Parkinson’s disease

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In a recently published study, Dr nature communication, Researchers investigated whether USP30 inhibition could serve as a disease-modifying therapy for Parkinson’s disease (PD) by increasing mitophagy and reducing α-synuclein (αSyn) pathology.

Study: Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model.  Image Credit: Chinnapong/Shutterstock.comStudy: Knockout or inhibition of USP30 protects dopaminergic neurons in a mouse model of Parkinson’s disease. Image Credit: Chinnapong/


Mitochondrial dysfunction is a key factor in PD, highlighting the importance of mitophagy, the selective degradation of mitochondrial dysfunction. Parkin mutations in autosomal recessive PD (AR-PD) impair mitophagy, and Parkin, another gene including PINK1 in which mutations cause AR-PD, plays an important role in the ubiquitination of mitochondrial proteins, essential for their autophagic degradation.

Furthermore, αSyn toxicity, associated with autosomal dominant PD (AD-PD), can induce mitochondrial impairment and reactive oxygen species production, suggesting a vicious cycle of dysfunction and αSyn accumulation.

Further studies are essential to comprehensively understand and validate the role of mitophagy, particularly through USP30 inhibition, in reducing α-synuclein toxicity and its therapeutic potential in PD.

About the study

In this study, researchers used an AAV1/2-A53T αSyn vector to induce synucleinopathy in mice, carefully selecting sample size and experimental endpoints based on previous studies.

Treatment groups were randomly assigned and analyzed with male and female mice as biological variables according to the National Institutes of Health’s (NIH’s) sex.

Ethical considerations were paramount, with all mouse studies adhering to strict regulations and institutional review board approval. Mice spanning different strains such as Mito-QC homozygous and USP30 knockout (KO) homozygous were housed in a controlled environment.

Extensive phenotyping of Usp30 KO mice has been performed and studies have included cell culture experiments with SH-SY5Y cells and human iPSC-derived dopaminergic neurons. These steps were crucial in exploring the potential of Usp30 KO and MTX115325 treatment to address PD pathology.

A variety of antibodies and vectors obtained from biotechnology companies have facilitated key procedures such as immunostaining and immunoblotting. The efficacy of the study was further confirmed by a strict protocol for stereotaxic vector injection, oral administration of the inhibitor MTX115325, and continuous monitoring of its blood concentrations.

Behavioral assessments, histological studies, mitophagy analysis, western blot analysis and dopamine measurements provide extensive insight. Additionally, biochemical and cell-based assays, detailed pharmacokinetics and brain cellular thermal shift assay (CETSA) analyzes were conducted.

Research findings were substantiated through rigorous statistical analysis, highlighting the thoroughness of the research methodology.

Results of the study

The present study successfully generated KO mice by deleting exon 4 of the USP30 gene. These mice were viable and exhibited no overt pathology, maintained normal Mendelian birth rates, and showed no significant health problems with aging. Interestingly, one-year-old USP30 KO mice showed resistance to fatty liver deposition compared to their wild-type counterparts.

The researchers further investigated the effect of USP30 KO on mitophagy in dopaminergic neurons. By crossing USP30 KO mice with mito-quality control (QC) reporter mice, they can effectively monitor mitophagy in vivo.

The study found a significant increase in the level of mitophagy in dopaminergic neurons of USP30 KO mice, particularly in the substantia nigra, cortex and hippocampus, compared to wild-type mice.

The study also explored the development of αSyn pathology and associated motor deficits in these mice. Immunostaining for phosphor-S129-αSyn, a pathological form of αSyn, showed that Usp30 KO mice had significantly reduced levels of this protein in their brains.

Additionally, colocalization analysis indicated that Usp30 depletion reduced the association of pathological S129-αSyn with mitochondria, suggesting a possible mechanism by which Usp30 KO reduces αSyn toxicity.

In this comprehensive study, the researchers investigated the protective role of KO against αSyn induced motor deficits. They used the cylinder test to assess motor function in post-AAV-A53T-SNCA mice such as Adeno-associated virus – alpha-synuclein with A53T mutation injection. The results showed that unilateral injection of AAV-Ev did not impair motor function in any mouse group.

However, AAV-A53T-SNCA injection led to motor dysfunction in wild-type (WT) and Mito-QC mice, as evidenced by decreased forelimb use contralateral to the injection site. Usp30 KO is significantly protected against these αSyn-induced motor deficits in both male and female mito-QC/Usp30 KO mice.

Furthermore, the study assessed the effect of Usp30 KO on αSyn-induced loss of dopaminergic neurites and terminals in the striatum. They observed a significant decrease in the density of tyrosine hydroxylase positive (TH+) terminals in the striatum of WT and mito-QC mice but not in Usp30 KO mice after AAV-A53T-SNCA injection.

Additionally, Usp30 KO appeared to protect against loss of striatal dopamine and its metabolites. These results demonstrate that Usp30 KO not only preserves the structural integrity of dopaminergic neurons but also maintains functional dopamine levels in the striatum.

The researchers also tested the efficacy of the brain-penetrating USP30 inhibitor, MTX115325. MTX115325 has demonstrated good oral bioavailability, central nervous system (CNS) penetration, and selectivity against other enzymes.

It effectively inhibits USP30 in biochemical assays and cellular models, increasing the ubiquitination of TOM20, a mitochondrial protein and USP30 substrate. In human dopaminergic neurons, MTX115325 increases TOM20-ubiquitylation, indicating its potential therapeutic application.


Finally, the study explored the effects of MTX115325 in the AAV-A53T-SNCA mouse model of PD, and the results mirrored those observed in Usp30 KO mice, with MTX115325 protecting against αSyn-induced loss of TH+ neurons and preserving striatal layers.

Furthermore, MTX115325 reduced phosphorylated S129-αSyn and astrocyte activation, further supporting its potential as a therapeutic agent in PD, and these comprehensive results highlight the therapeutic promise of USP30 inhibition in ameliorating PD pathology.

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