Altered dopamine release and monoamine transporters in Vps35 p.D620N knock-in mice

• Published in: NPJ Parkinson's Disease 2018-08, Vol.4 (1), p.27-11, Article 27
• Main Authors: Cataldi, Stefano, Follett, Jordan, Fox, Jesse D., Tatarnikov, Igor, Kadgien, Chelsie, Gustavsson, Emil K., Khinda, Jaskaran, Milnerwood, Austen J., Farrer, Matthew J.
• Format: Article
• Language: English
• Subjects: 631/378/548/1964; 692/617/375/1718; Biomedical and Life Sciences; Biomedicine; Dopamine; Neurology; Neurosciences; Parkinson's disease; Rodents
• ISSN: 2373-8057; 2373-8057
• DOI: 10.1038/s41531-018-0063-3

Vacuolar protein sorting 35 (VPS35) is a core component of the retromer trimer required for endosomal membrane-associated protein trafficking. The discovery of a missense mutation, Vps35 p.D620N implicates retromer dysfunction in the pathogenesis of Parkinson’s disease (PD). We have characterized a knock-in mouse with a Vps35 p.D620N substitution (hereafter referred to as VKI) at 3 months of age. Standardized behavioral testing did not observe overt movement disorder. Tyrosine hydroxylase (TH)-positive nigral neuron counts and terminal expression in striata were comparable across genotypes. Fast scan cyclic voltammetry revealed increased dopamine release in VKI striatal slices. While extracellular dopamine collected via striatal microdialysis of freely moving animals was comparable across genotypes, the ratio of dopamine metabolites to dopamine suggests increased dopamine turnover in VKI homozygous mice. Western blot of striatal proteins revealed a genotype-dependent decrease in dopamine transporter (DAT) along with an increase in vesicular monoamine transporter 2 (VMAT2), albeit independent of changes in other synaptic markers. The reduction in DAT was further supported by immunohistochemical analysis. The data show that the dopaminergic system of VKI mice is profoundly altered relative to wild-type littermates. We conclude early synaptic dysfunction contributes to age-related pathophysiology in the nigrostriatal system that may lead to parkinsonism in man. Neurogenetics: Impaired recycling impacts neurotransmission A mutation linked to late-onset Parkinson’s disease (PD) disrupts dopaminergic neurotransmission in mice. A study led by Matthew J. Farrer at the Centre for Applied Neurogenetics, University of British Columbia, Canada, examined the effects of a missense mutation in the gene encoding a core subunit of a complex required for recycling membrane-associated proteins, Vacuolar Protein Sorting 35 (VPS35; Vps35 ), in young adult mice. Although no significant effects on motor function or neurodegeneration were found, an increase in dopamine release and turnover in the dorsolateral striatum were observed in the mutant mice. Deficits in the transport and recycling of transporters required for dopamine re-uptake and storage may underlie these effects. Further analyses of Vps35 mutant mice could improve our understanding of the synaptic dysfunction that precedes neurodegeneration in PD.