Background
The parkin-interacting substrate (PARIS, also known as ZNF746) is a transcriptional repressor, whose accumulation and phosphorylation play central pathological roles in Parkinson's disease (PD). PARIS-induced transcriptional repression of PGC-1α or MDM4 contributes to mitochondrial dysfunction and p53-dependent neuron loss in PD. Despite the important role of PARIS in PD pathogenesis, unbiased transcriptomic profiles influenced by PARIS accumulation in dopaminergic neurons remain unexplored.
Conclusions
Conditional PARIS transgenic mice recapitulate robust and dopaminergic neuron-selective pathological features of PD, allowing the preclinical evaluation of antisymptomatic and disease-modifying therapeutic strategies within a couple of months. Based on this new PD mouse model, we provide unbiased bulk and single-nucleus transcriptomic profiles that are regulated by PARIS and potentially contribute to PD pathogenesis. A PD mouse model with flexible pathology induction capacity and a whole transcriptome could serve as a useful resource for translational PD research.
Methods
We engineered Tet-Off conditional transgenic mice expressing PARIS in dopaminergic neurons, driven by DAT-PF-tTA driver mice. The conditional PARIS transgenic mice were characterized by PD-associated pathologies, including progressive dopamine cell loss, neuroinflammation, PGC-1α repression, and mitochondrial proteome alteration. Motor impairment was assessed using pole and rotarod tests. L-DOPA and c-Abl inhibitors were administered to PARIS transgenic mice to evaluate their therapeutic efficacy. The transcriptomic profiles and gene ontology clusters were analyzed by bulk and single-nucleus RNA-seq for the ventral midbrains from PARIS transgenic and age-matched controls.
Results
Conditional dopaminergic PARIS expression in mice led to the robust and selective dopaminergic neuron degeneration, neuroinflammation, and striatal dopamine deficits, resulting in L-DOPA-responsive motor impairments. Consistent with the results of previous reports, PARIS suppressed dopaminergic PGC-1α expression, disturbed mitochondrial marker protein expression, and reduced COXIV-labeled mitochondria in dopamine neurons. Pharmacological inhibition of c-Abl activity in PARIS transgenic mice largely prevents PD-associated pathological features. Unbiased transcriptomic analysis revealed PARIS-regulated differentially expressed genes (DEGs), both collectively and in a cell-type-specific manner, along with enriched biological pathways linked to PD pathogenesis. Single-cell resolution transcriptomic analysis confirmed repression of PGC-1α and several mitochondria-related target genes in dopaminergic cells. Additionally, we identified distinct glial cell subpopulations and DEGs associated with PD pathogenesis. Conclusions: Conditional PARIS transgenic mice recapitulate robust and dopaminergic neuron-selective pathological features of PD, allowing the preclinical evaluation of antisymptomatic and disease-modifying therapeutic strategies within a couple of months. Based on this new PD mouse model, we provide unbiased bulk and single-nucleus transcriptomic profiles that are regulated by PARIS and potentially contribute to PD pathogenesis. A PD mouse model with flexible pathology induction capacity and a whole transcriptome could serve as a useful resource for translational PD research.