The E3 ubiquitin ligase Parkin ubiquitinates damaged mitochondria to tag them for autophagic degradation. Mutations in the PRKN gene are the most common cause of early-onset Parkinson’s disease (PD). These mutations induce dopaminergic neuron loss and both motor and non-motor symptoms. Despite PD being the fastest-growing neurodegenerative disorder globally, no disease-modifying therapies exist. Establishing new disease-relevant in-vivo models is crucial to the development of therapeutics, as classically-used neurotoxic models fail to mimic disease pathogenesis and progression.
Prkn knockout (KO) mice, though studied for over two decades, show minimal phenotypes without additional stressors, suggesting that mitochondrial dysfunction alone may be insufficient to induce PD-like pathology in mice.
To better understand disease mechanisms, we developed and characterised a novel Prkn KO (ΔATG) mouse and assessed it in two multiple-hit models: the Polg mitochondrial mutator mouse, and Bcl-x haploinsufficiency as we identified BCL-XL to be a critical vulnerability in human dopaminergic neuron survival. We evaluated motor performance using a combination of classical motor tests (Rotarod, pole test, grip strength) and sensitive techniques (CatWalk gait analysis), and brain pathology using lightsheet whole-brain imaging.
Our results demonstrate that these double mutant mice fail to robustly develop hallmark PD phenotypes, challenging their validity as PD models. Additionally, we highlight the limitations of standard behavioural assays in detecting subtle phenotypes typical of genetic models, compared to neurotoxic models. This work underscores the need for refined tools and multimodal approaches to evaluate the in vivo role of Parkin in PD pathophysiology and the complexity of modelling PD in mice.