The degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is a hallmark of Parkinson’s disease (PD). Nevertheless, little is known about the molecular signals that are altered in the prodromal phase in the adult striatum. To address this, we have used spatial transcriptomics and single-nucleus RNA sequencing to characterize the molecular events in mouse models of prodromal PD. We have used two different PD models: a) a progressive dopamine degeneration model of mitochondrial dysfunction (MitoPark mice), and b) a mild toxin model based on a low-dose unilateral 6-hydroxydopamine (6-OHDA) injection in the medial forebrain bundle (MFB). We have identified dysregulation in a number of genes, including activity-dependent genes such as Nr4a1, Rgs20, Syt6 and Egr1, across multiple cell types in the striatum.