Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem

Bertoglio, Daniele; Verhaeghe, Jeroen; wyffels, Leonie; Miranda, Alan; Stroobants, Sigrid; Mrzljak, Ladislav; Dominguez, Celia; Skinbjerg, Mette; Bard, Jonathan; Liu, Longbin; Muñoz-Sanjuán, Ignacio; Staelens, Steven

doi:10.2967/jnumed.121.262709

Cited by 24 publications

(30 citation statements)

References 44 publications

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“…Loss of synapses was reported with SV2A microPET in a heterozygous knock-in Q175DN mouse model of Huntington’s disease. The values were confirmed with [ 3 H]UCB-J autoradiography and SV2A immunofluorescence ( Bertoglio et al, 2021 ). SV2A microPET and autoradiography also revealed dose-dependent reductions of striatal SV2A binding in response to quinolinic acid injected in rat to induce an acute lesion model of Huntington’s disease ( Thomsen et al, 2021b ).…”

Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 56%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

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In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.

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Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 56%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

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“…EGR2 [99], ADCYAP1 [100], CHRNA7 [101], NRN1 [102], ETV5 [103], STXBP1 [104], CAMKK2 [105], VAMP2 [106], SYNGR1 [107], NOD2 [108], TLR2 [109], BRCA2 [110] and LEF1 [111] were previously reported to be critical for the development of bipolar disorder. Accumulating evidence shows that EGR2 [112], WNT1 [113], ARC (activity regulated cytoskeleton associated protein) [114], ADCYAP1 [115], SCN5A [116], RTN4R [117], CHRNA7 [118], NRGN (neurogranin) [119] [133], CDK5 [390], Griffioen et al [391], Larkin and Muchowski [392], Bailus et al [393], Sharma et al [394], Bondulich et al [395], Wong et al [396], Orozco-Díaz et al…”

Section: Tf-hub Gene Regulatory Network Constructionmentioning

confidence: 99%

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

Vastrad¹,

Vastrad²

2022

Preprint

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Parkinson's disease (PD) is the most commonly diagnosed neurodegenerative disorder Identification of novel prognostic and pathogenesis biomarkers plays a pivotal role in the management of the PD. Next generation sequencing (NGS) dataset from the GEO (Gene Expression Omnibus) database were used to identify differentially expressed genes (DEGs) in PD. Gene Ontology (GO) and REACTOME pathway enrichmental analyses were performed to elucidate the functional roles of the DEGs. Protein-protein interaction (PPI), modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network were established. The receiver operating characteristic curve (ROC) analysis was used to explore the diagnostic values of hub genes in PD. In total, 957 DEGs were identified, of which 478 were up regulated genes and 479 were down regulated genes. GO and pathway enrichment analysis results revealed that the up regulated genes were mainly enriched in nervous system development, cell junction, transporter activity and neuronal system, whereas down regulated genes were mainly enriched in response to stimulus, cell periphery, identical protein binding and immune system. The top hub genes in the constructed PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network were OTUB1, PPP2R1A, AP2M1, PIN1, USP11, CDK2, IQGAP1, NEDD4, VIM and CDK1. Furthermore, ROC analysis showed that hub genes were having good diagnostic values. We identified a series of essential genes along with the pathways that were most closely related with PD initiation and progression. Our results provide a more detailed molecular mechanism for the advancement of PD, shedding light on the potential biomarkers and therapeutic targets.

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“…In the homozygous SAP90/PSD-95-associated protein 3 (Sapap3) knockout mouse model for obsessive-compulsive disorder, 14% lower volume of distribution ( V T ) using image-derived input function (IDIF) was observed in striatum based on the Logan reference method ( Glorie et al, 2020 ). The heterozygous Q175DN knock-in mice for Huntington’s disease (HD) demonstrated 20% lower V T(IDIF) in striatum ( Bertoglio et al, 2021 ). For rat SV2A PET studies, Thomsen et al (2021) generated PD and HD lesion by the local injections of 6-OHDA and quinolinic acid (QA), respectively, in the rat striatum.…”

Section: Introductionmentioning

confidence: 99%

PET Imaging of Synaptic Density: Challenges and Opportunities of Synaptic Vesicle Glycoprotein 2A PET in Small Animal Imaging

et al. 2022

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The development of novel PET imaging agents for synaptic vesicle glycoprotein 2A (SV2A) allowed for the in vivo detection of synaptic density changes, which are correlated with the progression and severity of a variety of neuropsychiatric diseases. While multiple ongoing clinical investigations using SV2A PET are expanding its applications rapidly, preclinical SV2A PET imaging in animal models is an integral component of the translation research and provides supporting and complementary information. Herein, we overview preclinical SV2A PET studies in animal models of neurodegenerative disorders and discuss the opportunities and practical challenges in small animal SV2A PET imaging. At the Yale PET Center, we have conducted SV2A PET imaging studies in animal models of multiple diseases and longitudinal SV2A PET allowed us to evaluate synaptic density dynamics in the brains of disease animal models and to assess pharmacological effects of novel interventions. In this article, we discuss key considerations when designing preclinical SV2A PET imaging studies and strategies for data analysis. Specifically, we compare the brain imaging characteristics of available SV2A tracers, i.e., [11C]UCB-J, [18F]SynVesT-1, [18F]SynVesT-2, and [18F]SDM-16, in rodent brains. We also discuss the limited spatial resolution of PET scanners for small brains and challenges of kinetic modeling. We then compare different injection routes and estimate the maximum throughput (i.e., number of animals) per radiotracer synthesis by taking into account the injectable volume for each injection method, injected mass, and radioactivity half-lives. In summary, this article provides a perspective for designing and analyzing SV2A PET imaging studies in small animals.

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Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem

Cited by 24 publications

References 44 publications

Synaptic Vesicle Glycoprotein 2A: Features and Functions

Synaptic Vesicle Glycoprotein 2A: Features and Functions

Bioinformatics and next generation sequencing data analysis to identify key genes and pathways influencing in Parkinson’s disease

PET Imaging of Synaptic Density: Challenges and Opportunities of Synaptic Vesicle Glycoprotein 2A PET in Small Animal Imaging

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