USP30 Parkinson’s Disease Program

Disease Indication

Parkinson’s Disease

Parkinson’s disease (PD) is a chronic, degenerative neurological disorder that affects one in 100 people over the age of 60. PD is the second most common neurodegenerative disease, with prevalence more than doubling over the last 2 decades. There is no objective test or biomarker for Parkinson’s disease, so the rate of misdiagnosis can be relatively high. As a result, estimates of the number of people living with the disease vary, although recent research indicates that at least one million people in the United States, and more than five million worldwide, suffer from Parkinson’s disease.

Loss of dopaminergic neurons in the substantia nigra impair basal ganglia circuits which result in characteristic clinical signs of slow movement, tremor and rigidity. Whilst PD is likely to be multifactorial, mitochondrial dysfunction is recognized as a key pathophysiological mechanism in PD. Loss of function mutations in Parkin, PINK1 and protein deglycase DJ-1 predispose to development of early onset PD. Alpha-synuclein, a key potential pathogenic protein in PD, directly interacts with mitochondria at TOM20 and functionally at mitochondrial complex I, inhibiting mitochondrial function. Furthermore, oxidative stress output from mitochondria can oxidize dopamine which further causes alpha-synuclein aggregation and neurotoxicity.

Proposed Mechanism of Action and Therapeutic Rationale

USP30 has been highlighted as a promising new target in the Central Nervous System (CNS) arena (Bingol et al., 2014 Nature 510: p370) based on effects on the Parkin pathway, which is mutated in certain Parkinson’s patients. Given that adult neurons do not divide, removal of dysfunctional mitochondria is essential to prevent impaired neuronal function and aid survival. Failure of mitochondrial quality control may lead to degeneration of the highly active substantia nigra neurons in the brain, a pathological mechanism that results in Parkinson’s disease. USP30 directly antagonizes the Parkin/PINK1 pathway of mitochondrial quality control. Genetic knockdown of USP30 can enhance mitophagy during stress and can rescue stress-induced mitophagy when Parkin/PINK1 activities are impaired. Small molecule USP30 inhibition promotes mitophagy in vitro and in vivo enhancing this quality control through inhibition of USP30 could therefore be beneficial in treating Parkinson’s. (Nature Comminucations)

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