Abstract
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.
Highlights
Parkinson’s disease (PD) is an age-related neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons and Lewy pathology.[1]
Dominantly-inherited, late-onset parkinsonism has recently been linked to an aspartate to asparagine substitution in vacuolar protein sorting 35 (VPS35 p.D620N).[4,5]
Wild-type (WT) and mutant allele-specific Vps[35] mRNA expression was equimolar and unaltered by gene targeting in Vps35 p.D620N knockin mouse model (VKI) animals (Fig. 1c, 1-way ANOVA p = 0.95)
Summary
Parkinson’s disease (PD) is an age-related neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons and Lewy pathology.[1]. Dominantly-inherited, late-onset parkinsonism has recently been linked to an aspartate to asparagine substitution in vacuolar protein sorting 35 (VPS35 p.D620N).[4,5] Affected subjects in >61 unrelated families have been described with a clinical syndrome indistinguishable from idiopathic PD.[6] VPS35, VPS26, and VPS29 are structural components of the retromer trimer[7,8] that complex with a pair of sorting nexins to recycle transmembrane cargo to the cell surface or trans-Golgi network.[9] Within the synapse, the retromer recycles neurotransmitter receptors including β-adrenergic, AMPA-type glutamate, and D1-type dopamine receptors.[10,11,12,13,14,15]
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