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 LRRK2 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9927849 | PMC |
| http://dx.doi.org/10.1002/brb3.2886 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Widespread Distribution of α-Synuclein Oligomers in -related Parkinson's Disease.
bioRxiv
December 2024
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Mutations in leucine-rich repeat kinase 2 () are the most common cause of familial and sporadic Parkinson's disease (PD). While the clinical features of -PD patients resemble those of typical PD, there are significant differences in the pathological findings. The pathological hallmark of definite PD is the presence of α-synuclein (αSYN)-positive Lewy-related pathology; however, approximately half of -PD cases do not have Lewy-related pathology.
View Article and Find Full Text PDFThe Parkinson's disease (PD)-linked protein Leucine-Rich Repeat Kinase 2 (LRRK2) consists of seven domains, including a kinase and a Roc G domain. Despite the availability of several high-resolution structures, the dynamic regulation of its unique intramolecular domain stack is nevertheless still not well understood. By in-depth biochemical analysis, assessing the Michaelis-Menten kinetics of the Roc G domain, we have confirmed that LRRK2 has, similar to other Roco protein family members, a K value of LRRK2 that lies within the range of the physiological GTP concentrations within the cell.
View Article and Find Full Text PDFArticle Synopsis
- Research indicates that SARS-CoV-2 infection can increase the risk of developing parkinsonian symptoms when combined with the mitochondrial toxin MPTP, particularly in genetically modified mice expressing human ACE2 receptors.
- The study found that while both mRNA and protein-based vaccines can mitigate neurodegeneration in wild-type (WT) mice, only the protein-based vaccine was effective in protecting G2019S LRRK2 mutant mice from SARS-CoV-2 related neurological damage.
- Overall, the findings emphasize how environmental toxins and genetic predisposition contribute to the development of neurological diseases after viral infections, as well as the potential protective effects of vaccines.
The kinase LRRK2 is required for the physiological function and expression of the glial glutamate transporter EAAT2 (SLC1A2).
J Neurochem
January 2025
Department of Biotechnology and Life Sciences, Laboratory of Cellular and Molecular Physiology, University of Insubria, Varese, Italy.
Article Synopsis
- * EAAT2 dysfunction is linked to several neurodegenerative diseases, including Alzheimer's and Parkinson's, with specific mutations in LRRK2, particularly Gly2019Ser, reducing EAAT2 expression.
- * This study reveals that LRRK2 is essential for the stability and function of EAAT2, suggesting its role in preventing neuronal damage from excessive excitatory signals, but does not affect the function of other NTTs.
PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner.
Cell Death Dis
October 2024
Department of Biology, University of Padova, Padova, PD, Italy.
P21 activated kinase 6 (PAK6) is a serine-threonine kinase with physiological expression enriched in the brain and overexpressed in a number of human tumors. While the role of PAK6 in cancer cells has been extensively investigated, the physiological function of the kinase in the context of brain cells is poorly understood. Our previous work uncovered a link between PAK6 and the Parkinson's disease (PD)-associated kinase LRRK2, with PAK6 controlling LRRK2 activity and subcellular localization via phosphorylation of 14-3-3 proteins.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!