In vivooverexpression of synaptogyrin-3 promotes striatal synapticdopamineuptakein LRRK2R1441G mutant mouse model of Parkinson's disease.

Abstract

Leucine-rich repeat kinase 2 (LRRK2) mutation is a common genetic risk factor of Parkinson's disease (PD). Presynaptic dysfunction is an early pathogenic event associated with dopamine (DA) dysregulation in striatum of the brain. DA uptake activity of DA uptake transporter (DAT) affects synaptic plasticity andmotorand non-motorbehavior. Synaptogyrin-3(SYNGR3)is part of the synaptogyrin family, especially abundant in brain. Previousin vitrostudies demonstrated interaction between SYNGR3 and DAT.Reduced SYNGR3 expression was observed inhuman PD brainswith unclear reasons. Here, wefurtherexplored whether inducing SYNGR3 expression can influence(i) cellular DA uptake using differentiated humanSH-SY5Yneuronalcells, (ii) striatal synaptosomalDA uptakein amutant LRRK2R1441G knockin mouse modelof PD, and (iii) innate rodentbehaviorusing the marble burying test. Young LRRK2 mutant mice exhibited significantly lower SYNGR3 levels in striatum compared to age-matched wild-type (WT) controls, resembling level in aged WT mice. SYNGR3 is spatially co-localized with DAT at striatal presynaptic terminals, visualized by immuno-gold transmission electron microscopyand immunohistochemistry. Their protein-protein interaction was confirmed by co-immunoprecipitation. Transient overexpression of SYNGR3 in differentiated SH-SY5Y cellsincreasedcellular DA uptake activity without affecting total DAT levels. Inducing SYNGR3 overexpression by adeno-associated virus-7 (AAV7) injectionin vivointo striatum increasedex vivosynaptosomal DA uptakein LRRK2 mutant mice and improved theirinnatemarble buryingbehavior. Brain SYNGR3expressionmay be an important determinant to striatal DA homeostasisand synaptic function.Ourpreliminarybehavioraltest showed improved innatebehaviorafter SYNGR3 overexpression in LRRK2 mutant mice, advocating further studies to determine the influence of SYNGR3 in thepathophysiology of DA neuronsin PD.