fbpx USP30 a valid therapeutic target | Progress In Mind

USP30 a valid therapeutic target

The idea that mitochondrial dysfunction is implicated in Parkinson’s Disease is not new, but recent work has placed USP30 at the heart of ubiquitin-mediated quality control of mitochondria. Paul Thompson and colleagues (Mission Therapeutics, Cambridge, UK) aim to validate USP30 as a therapeutic target in PD and to develop potent small molecule inhibitors. VPS35, discussed by Darren Moore, is another potential target.

The family of deubiquitylating enzymes (DUBs) counteract the ubiquitin lipases which signal proteins and organelles for destruction. The working hypothesis is that by inhibiting DUBs we can promote the clearance of unwanted or dysfunctional proteins or organelles such as the pathogenic protein aggregates present in neurodegenerative CNS disease, Paul Thompson (Mission Therapeutics, Cambridge, UK) told the Michael J Fox Foundation’s 11th Annual Therapeutics Conference.

One DUB in particular has attracted the interest of Dr Thompson and colleagues. USP30 (ubiquitin carboxyl-terminal hydrolase 30) is localized to the outer mitochondrial membrane, meaning that its inhibition should not lead to unwanted ubiquitination across the cell. A second advantage is the substantial homology across humans and animal species used in drug development.

USP30 inhibition can produce dose-dependent neuroprotection

Does too little mitophagy contribute to disease?

USP30 inhibitors can promote mitophagy in HeLa cells exposed to mitochondrial depolarizing agents, and work has been extended into dopaminergic cell types relevant to PD. In vivo, the MPTP animal model of substantia nigra degeneration is attractive since it essentially involves induction of mitochondrial dysfunction. In this model, use of a USP30 inhibitor produces dose-dependent neuroprotection. Efforts are under way to determine whether this protection is due to mitophagy.

A further piece of evidence validating USP30 as a potential target is that young USP30 knock-out animals show higher levels of dopamine in the striatum than wild-type animals. We still need to clarify whether this difference persists into old age.

Moving closer to PD as it occurs in humans, efforts are being made to investigate the effect of USP inhibitors on mitochondrial function and mitophagy deficits in patient-derived DA neurons. It seems likely that too little mitophagy contributes to various diseases. An unresolved question is whether there might also be problems with too much mitophagy.

VPS35 is another potential target

VPS35 (Vacuolar protein sorting-associated protein 35) point mutations have recently been established as a cause of late-onset PD, Darren Moore (Van Andel Research Institute, Grand Rapids, Michigan, USA) reported at the same session on emerging therapeutic targets.

VPS35 is a key component of the retromer complex that traffics various membrane-bound cargoes from endosomes to the trans-Golgi network. The common pathogenic mutation can result in reduced binding to the WASH complex but it is not clear whether this is true in the brain.

VPS35 mutation is associated with tau pathology in the hippocampus

What we do know is that overexpression of mutant (D620N) VPS35 in rodent brain induces dopaminergic neurodegeneration in the substantia nigra and pathology. Data from knock-out mice suggest that alpha-synuclein is not required for this neuronal damage to occur and that it is not playing a key role downstream from VPS35.  Experiments undertaken by Dr Moore and colleagues provide no evidence that VPS35 is downstream of alpha-synuclein, or that its overexpression can rescue rats from alpha-synuclein induced DA cell loss.

Intriguingly, although VPS35 D620N mutation does not seem related to alpha-synuclein pathology in the knock-in mouse brain, there is evidence of associated tau pathology in the hippocampus. There are plans to look at human post mortem brains to see if these also show tauopathy.

You are leaving Progress in Mind
Please confirm your email
We have just sent you an email, with a confirmation link.
Before you can gain full access - you need to confirm your email.
The information on this site is exclusively intented for health care professionals.
All the information included in the Website is related to products of the local market and, therefore, directed to health professionals legally authorized to prescribe or dispense medications with professional practice. The technical information of the drugs is provided merely informative, being the responsibility of the professionals authorized to prescribe drugs and decide, in each concrete case, the most appropriate treatment to the needs of the patient.
Register for access to Progress in Mind in your country