VMAT2 Inhibitors in Neuropsychiatric Disorders

Tarakad, Arjun; Jimenez-Shahed, Joohi

doi:10.1007/s40263-018-0580-y

Cited by 22 publications

(17 citation statements)

References 100 publications

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“…Therefore, we focused on key genes and components of each pathway that also are shown in the literature to be altered in HD and/or other neurodegenerative disorders. Expression levels of Vesicular monoamine transporter 2 (VMAT2), a transporter of common neurotransmitters such as dopamine and used as a therapeutic strategy for hyperkinetic disorders, were comparable in 79Q vs. 18Q [50, 51] (Figure 4A). 79Q displayed significant downregulations in hypocretin neuropeptide precursor ( Hcrt ), diazepam-binding inhibitor ( Dbi ), Ddc, Hdc, and Th in 79Q compared to 18Q (Figure 4B-D, F-G).…”

Section: Resultsmentioning

confidence: 99%

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

Dickson

Dwijesha

Andersson

et al. 2022

Preprint

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Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington's disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. In the present study, we investigated whether transcriptional changes would be part of hypothalamic pathology induced by the disease-causing huntingtin (HTT) protein. We performed microarray analysis using the Affymetrix platform on total hypothalamic RNA isolated from two HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. To analyze microarray datasets (34760 variables) and obtain functional implications of differential expression patterns, we used Linear Models for Microarray Data (limma) followed by Gene Set Enrichment Analysis (GSEA) using ClusterProfiler. Limma identified 735 and 721 significantly differentially expressed genes (adjusted p < 0.05) in hypothalamus of AAV datasets wtHTT vs control and mHTT vs control. In contrast, for BACHD datasets and the AAV mHTT vs. wtHTT dataset, none of the genes were differentially expressed (adjusted p-value > 0.05 for all probe IDs). In AAV groups, from the combined limma with GSEA using ClusterProfiler, we found both shared and unique gene sets and pathways for mice with wtHTT overexpression compared to mice with mHTT overexpression. mHTT caused widespread suppression of neuroendocrine networks, as evident by GSEA enrichment of GO-terms related to neurons and/or specific neuroendocrine populations. Using qRT-PCR, we confirmed that mHTT overexpression caused significant downregulation of key enzymes involved in neuropeptide synthesis, including histidine and dopa decarboxylases, compared to wtHTT overexpression. Multiple biosynthetic pathways such as sterol synthesis were among the top shared processes, where both unique and shared genes constituted leading-edge subsets. In conclusion, mice with targeted overexpression of HTT (wtHTT or mHTT) in the hypothalamus show dysregulation of pathways, of which there are subsets of shared pathways and pathways unique to either wtHTT or mHTT overexpression.

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Section: Resultsmentioning

confidence: 99%

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

Dickson

Dwijesha

Andersson

et al. 2022

Preprint

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“…This affects the morphology and function of platelet dense granules and thereby also of platelet function. Of note, there exist VMAT2 inhibitors such as tetrabenazine that are used for treating tardive dyskinesia and Huntington chorea . It is known that tetrabenazine controls the uptake of 5‐HT into platelet dense granules .…”

Section: Discussionmentioning

confidence: 99%

A novel missense variant in SLC18A2 causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets

et al. 2019

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Background Brain monoamine vesicular transport disease is an infantile onset neurodevelopmental disorder caused by variants in SLC18A2 , which codes for the vesicular monoamine transporter 2 (VMAT2) protein, involved in the transport of monoamines into synaptic vesicles and of serotonin into platelet dense granules. Case presentation The presented case is of a child, born of healthy consanguineous parents, who exhibited hypotonia, mental disability, epilepsy, uncontrolled movements, and gastrointestinal problems. A trial treatment with L‐DOPA proved unsuccessful and the exact neurological involvement could not be discerned due to normal metabolic and brain magnetic resonance imaging results. Platelet studies and whole genome sequencing were performed. At age 4, the child's platelets showed a mild aggregation and adenosine triphosphate secretion defect that could be explained by dysmorphic dense granules observed by electron microscopy. Interestingly, the dense granules were almost completely depleted of serotonin. A novel homozygous p.P316A missense variant in VMAT2 was detected in the patient and the consanguineous parents were found to be heterozygous for this variant. Although the presence of VMAT2 on platelet dense granules has been demonstrated before, this is the first report of defective platelet dense granule function related to absent serotonin storage in a patient with VMAT2 deficiency but without obvious clinical bleeding problems. Conclusions This study illustrates the homology between serotonin metabolism in brain and platelets, suggesting that these blood cells can be model cells for some pathways relevant for neurological diseases. The literature on VMAT2 deficiency is reviewed.

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“…Tardive dyskinesia, a movement disorder caused by dopamine hypersensitivity, is commonly observed in patients after antipsychotic treatment with DRBAs (dopamine-receptor-blocking agents). Inhibition of the vesicular monoamine transporter 2 (SLC18A2) decreases synaptic dopamine concentration by blocking the uptake of dopamine into synaptic vesicles and facilitating its degradation by cytosolic enzymes …”

Section: Slcs In Human Diseasementioning

confidence: 99%

The Druggability of Solute Carriers

et al. 2019

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The transport of materials across membranes is a vital process for all aspects of cellular function, including growth, metabolism, and communication. Protein transporters are the molecular gates that control this movement and serve as key points of regulation for these processes, thus representing an attractive class of therapeutic targets. With more than 400 members, the solute carrier (SLC) membrane transport proteins are the largest family of transporters, yet, they are pharmacologically underexploited relative to other protein families and many of the available chemical tools possess suboptimal selectivity and efficacy. Fortuitously, there is increased interest in elucidating the physiological roles of SLCs as well as growing recognition of their therapeutic potential. This Perspective provides an overview of the SLC superfamily, including their biochemical and functional features, as well as their roles in various human diseases. In particular, we explore efforts and associated challenges toward drugging SLCs, as well as highlight opportunities for future drug discovery.

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VMAT2 Inhibitors in Neuropsychiatric Disorders

Cited by 22 publications

References 100 publications

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

A novel missense variant in SLC18A2 causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets

The Druggability of Solute Carriers

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