MTX115325 (Example 1) is an orally active, brain-penetrating USP30 inhibitor (IC 50 =12 nM) with neuroprotective activity. MTX115325 increases ubiquitination (EC 50 =32 nM) of the mitochondrial outer membrane protein TOM20 (a USP30 substrate), increasing mitophagy. MTX115325 prevents dopaminergic neuron loss and preserves striatal dopamine.