Session Information
Date: Wednesday, September 25, 2019
Session Title: Physiology and Pathophysiology
Session Time: 1:15pm-2:45pm
Location: Les Muses, Level 3
Objective: To study the effects of DNAJC13 p.Asn855Ser mutant gene dysfunction in a physiological context, and to help define molecular mechanisms for disease, using a novel DNAJC13 p.Asn855Ser knock-in (DKI) mouse model.
Background: Parkinson’s disease (PD) is a common neurodegenerative disorder for which genetic studies have discovered multiple causative genetic mutations to highlight convergent cellular pathways. In 2014 DNAJC13 (coding receptor-mediated endocytosis-8 (RME-8)) was linked to late-onset autosomal dominant late-onset parkinsonism in a Mennonite multi-incident kindred with post-mortem SNpc neuronal loss and Lewy body (LB) pathology, and in five additional patients, three of which have a family history of disease (1,2). Although the underlying mechanism for disease is unknown, prior studies on DNAJC13 p.Asn855Ser describe impaired recycling of membrane-associated receptors and α-synuclein accumulation [3,4]. To study the effects of DNAJC13 p.Asn855Ser mutant gene dysfunction in a physiological context, we have established a DNAJC13 p.Asn855Ser knock-in (DKI) mouse model.
Method: Generation of the DNAJC13 p.N855S substitution in a knock-in (KI) mouse using Cre-loxP recombination. Biochemical, physiological and behavioral differences were examined in KI vs wild-type (WT) mice, with emphasis on synaptic vesicular trafficking, and transporter activity in the striatum.
Results: Heterozygous DNAJC13 p.N855S KI mice have significant behavioral phenotypes (including open field locomotion, grip strength and balance/coordination) at different ages compared to WT littermates. We observed differences in expression of synaptic vesicular proteins and membrane transporters (α-synuclein, VAMP2, VGluT1 and DAT) by immunofluorescence confocal imaging and/or protein biochemistry analysis. Levels of neurotransmitters and markers of pathology including ((p-)α-synuclein, (p-)Tau, P62, Iba-1, APP, GFAP.) were analyzed by HPLC and immunolabeling, respectively.
Conclusion: Overall, the genetic and functional evidence for the pathogenicity of DNAJC13 p.N855S in PD is compelling. DNAJC13 p.N855S KI mice have significant behavioral phenotypes (including open field locomotion, grip strength and balance/coordination), loss of synaptic machinery and accumulation of alpha-synuclein.DNAJC13 is one of five DNAJC co-chaperones implicated in Parkinsonism. Further study of DNAJC13 is needed and appears central to the molecular pathogenesis of PD.
References: 1. Vilarino-Guell, C., et al., DNAJC13 mutations in Parkinson disease. Hum Mol Genet, 2014. 23(7): p. 1794-801. 2. Gustavsson, E.K., et al., DNAJC13 Genetic Variants in Parkinsonism. Movement Disorders, 2015. 30(2): p. 273-278. 3. Yoshida, S., et al., Parkinson’s disease-linked DNAJC13 mutation aggravates alpha-synuclein-induced neurotoxicity through perturbation of endosomal trafficking. Hum Mol Genet, 2018. 27(5): p. 823-836. 4. Xhabija, B. and P.O. Vacratsis, Receptor-mediated Endocytosis 8 Utilizes an N-terminal Phosphoinositide-binding Motif to Regulate Endosomal Clathrin Dynamics. J Biol Chem, 2015. 290(35): p. 21676-89.
To cite this abstract in AMA style:
J. Follett, J. Fox, E. Gustavsson, M. Farrrer. DNAJC13 in Parkinson’s disease; characterization of the p.N855S knock-in mouse model [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/dnajc13-in-parkinsons-disease-characterization-of-the-p-n855s-knock-in-mouse-model/. Accessed December 1, 2024.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/dnajc13-in-parkinsons-disease-characterization-of-the-p-n855s-knock-in-mouse-model/