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. Accumulating evidence shows that this α-synucleinopathy leads to mitochondrial dysfunction, which drives the progression of dopaminergic neurodegeneration in PD patients and animal models. These observations are reinforced by the fact that PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria (“mitophagy”) by inducing ubiquitination of mitochondrial proteins, a process counteracted by deubiquitination via USP30. To understand how αSyn accumulation and toxicity relate to mitophagy, we created Usp30 knockout (KO) mice and pharmacological USP30 inhibitors. We now show that Usp30 KO mice are viable, show no overt pathologies and are protected against αSyn induced pathology. We further show that USP30 loss leads to increased levels of mitophagy in dopaminergic neurons and attenuates dopaminergic neuronal loss and the behavioral deficits induced by αSyn following stereotaxic injection of AAV-A53T-SNCA into the substantia nigra (SN). Moreover, this functional rescue is associated with significantly decreased pathological phospho-S129 αSyn in dopaminergic neurons of the SN in Usp30 KO mice. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325 (USP30i), with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.

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. Accumulating evidence shows that this α-synucleinopathy leads to mitochondrial dysfunction, which drives the progression of dopaminergic neurodegeneration in PD patients and animal models. These observations are reinforced by the fact that PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria (“mitophagy”) by inducing ubiquitination of mitochondrial proteins, a process counteracted by deubiquitination via USP30. To understand how αSyn accumulation and toxicity relate to mitophagy, we created Usp30 knockout (KO) mice and pharmacological USP30 inhibitors. We now show that Usp30 KO mice are viable, show no overt pathologies and are protected against αSyn induced pathology. We further show that USP30 loss leads to increased levels of mitophagy in dopaminergic neurons and attenuates dopaminergic neuronal loss and the behavioral deficits induced by αSyn following stereotaxic injection of AAV-A53T-SNCA into the substantia nigra (SN). Moreover, this functional rescue is associated with significantly decreased pathological phospho-S129 αSyn in dopaminergic neurons of the SN in Usp30 KO mice. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325 (USP30i), with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.