Objective: This project aimed to characterize the first-ever transgenic ATP13A2 knockout rat model to elucidate the underlying mechanisms of ATP13A2-associated pathology.

Background: Most Parkinson’s disease (PD) cases are sporadic, but 10-15% of patients have a familial type. The ATP13A2 gene encodes a transmembrane lysosomal P5-type ATPase recently identified as a lysosomal polyamine exporter. Mutations in the ATP13A2 gene were identified as the cause of Kufor-Rakeb syndrome, a juvenile-onset form of PD. Developing a relevant and predictable PD model is still an unmet need for the research community to better understand the mechanisms underlying the pathology and to identify and validate therapeutic strategies.

Method: To this end, we performed a comprehensive longitudinal characterization of symptoms and associated neuropathology in this animal model of PD, offering new insights into the pathogenesis of PD and a potential tool for testing and validating therapeutic approaches.

To assess whether deletion of the ATP13A2 gene in rats can replicate human pathology, we followed developmental milestones as well as longitudinal motor assessment to evaluate akinesia and bradykinesia using the “stepping” test every 3 months up to 12 months of age and also assessed fine motor skills using a reaching task as these deficits are one of the first motor symptoms occurred in PD patients. We also evaluated whether a viral-mediated overexpression of α-synuclein exacerbates motor and cellular deficits in ATP13A2-KO rats.

Results: ATP13A2 KO rats displayed age-dependent fine motor skills deficits and impaired locomotor habituation similar to those observed in parkinsonian patients at the early stage of motor symptom onset. We detected significant differences in astroglial activation in the substantia nigra of ATP13A2 KO, consistent with the pathology seen in PD brain patients. Overexpression of mutated human alpha-synuclein in substantia nigra showed a significant increase in protein expression without a significant effect on genotype. Additional analyses are ongoing to understand the contribution of lysosomal ATP13A2 protein in the pathogenesis of PD.

Conclusion: Furthermore, we hope to better understand the lysosomal-related mechanisms and the lysosomal ATP13A2 protein in PD pathogenesis that might open new therapeutic opportunities for slowing down the dopaminergic in patients with Parkinson’s disease.

« Back to 2024 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-characterization-of-an-atp13a2-knockout-rat-model-of-parkinsons-disease/