Objective: To characterize the Dnajc13 p.N860S mouse model of familial Parkinson’s disease

Background: DNAJC13/RME-8 is a large, multi-domain molecular co-chaperone that facilitates membrane recycling and cargo sorting of endocytosed proteins. DNAJ proteins contain a central J-domain, which binds and stimulates the ATPase activity of HSC70/HSP70 to facilitate protein folding, degradation, complex assembly or translocation across membranes. In 2014, a c.2564A>G (p.N855S) mutation in DNAJC13 was linked to late-onset autosomal dominant Parkinson’s disease in a large multi-incident family. We generated DNAJC13 p.N860S knock-in (DKI) mice, the murine equivalent of the human p.N855S mutation, and characterized their phenotype.

Method: To assess the impact of the Dnajc13 p.N860S mutation on the dopaminergic system in vivo, we employed a combination of behavioral, biochemical, and imaging techniques including electron microscopy (TEM) on WT and Dnajc13 p.N860S knock-in mice. HPLC and fast-scan cyclic voltammetry were used to interrogate dopaminergic dysfunction associated with Dnajc13 p.N860S while primary neuron culture and alpha-synuclein seeding assays were used to assess the impact of increased alpha-synuclein protein.

Results: We have previously shown that expression of DNAJC13 p.N860S knock-in (DKI) mice, the murine equivalent of the human p.N855S mutation, in cultured primary cortical neurons causes endosomal trafficking deficits. In the brains of DKI animals, we observe an intact nigrostriatal network, monoamine content and metabolism in the striatum. Basic motor testing reveals a subtle motor phenotype characterized by increased freezing episodes and an inability to complete fine motor tasks when compared to WT littermates. Biochemically, DKI mice have a compromised endo-lysosomal system in turn accelerating the mishandling of alpha-synuclein, a protein implicated in the pathogenesis of PD.

Conclusion: DNAJC13 p.N860S knock-in mice represent a model of late-onset familial PD through physiological over-expression of alpha-synuclein. Further studies, including the exacerbation of phenotypes with age, are warranted especially to to explore the potential effect of DNAJC13 p.N860S on synuclein spreading and dopaminergic cell loss.

This work was supported by the National institute of Health (Award # 1R21NS135376-01; M.J.F) and the by the Lee and Lauren Fixel Chair in Parkinson’s research to M.J.F. [2020-2024].

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterization-of-the-dnajc13-p-n860s-mouse-model-a-physiological-model-of-alpha-synuclein-overexpression/