In vivo overexpression of synaptogyrin-3 promotes striatal synaptic dopamine uptake in LRRK2R1441G mutant mouse model of Parkinson's disease

Philip Wing Lok Ho (Corresponding Author), Lingfei Li, Hui Fang Liu, Zoe Yuen Kiu Choi, Eunice Eun Seo Chang, Shirley Yin Yu Pang, Yasine Malki, Chi Ting Leung, Michelle Hiu Wai Kung, David Boyer Ramsden, Shu Leong Ho (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

2 Citations (Scopus)

Abstract

Background: 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 and motor and non-motor behavior. Synaptogyrin-3 (SYNGR3) is part of the synaptogyrin family, especially abundant in brain. Previous in vitro studies demonstrated interaction between SYNGR3 and DAT. Reduced SYNGR3 expression was observed in human PD brains with unclear reasons. Methods: Here, we further explored whether inducing SYNGR3 expression can influence (i) cellular DA uptake using differentiated human SH-SY5Y neuronal cells, (ii) striatal synaptosomal DA uptake in a mutant LRRK2R1441G knockin mouse model of PD, and (iii) innate rodent behavior using the marble burying test. Results: 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 microscopy and immunohistochemistry. Their protein–protein interaction was confirmed by co-immunoprecipitation. Transient overexpression of SYNGR3 in differentiated SH-SY5Y cells increased cellular DA uptake activity without affecting total DAT levels. Inducing SYNGR3 overexpression by adeno-associated virus-7 (AAV7) injection in vivo into striatum increased ex vivo synaptosomal DA uptake in LRRK2 mutant mice and improved their innate marble burying behavior. Conclusion: Brain SYNGR3 expression may be an important determinant to striatal DA homeostasis and synaptic function. Our preliminary behavioral test showed improved innate behavior after SYNGR3 overexpression in LRRK2 mutant mice, advocating further studies to determine the influence of SYNGR3 in the pathophysiology of DA neurons in PD.

Original languageEnglish
Article numbere2886
JournalBrain and Behavior
Volume13
Issue number2
DOIs
Publication statusPublished - Feb 2023

Keywords

  • behavioral test
  • dopamine uptake
  • LRRK2 mutation
  • SYNGR3

ASJC Scopus subject areas

  • Behavioral Neuroscience

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