hVMAT2: A Target of Individualized Medication for Parkinson's Disease

Xiong, Nian; Li, Nuomin; Martin, Eden R.; Yu, Jinlong; Li, Jie; Liu, Jing; Lee, David Yue Wei; Isacson, Ole; Vance, Jeffery M.; Qing, Hong; Wang, Tao; Lin, Zhicheng

doi:10.1007/s13311-016-0435-5

Cited by 13 publications

(12 citation statements)

References 60 publications

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“…Until recently, analysis of the gene (SLC18A2) for VMAT2 within Parkinson’s disease cohorts was unable to conclude that variants in SLC18A2 result in increased likelihood of Parkinson’s disease 31 . However, a study published by Xiong et al in 2016 identified two polymorphisms in SLC18A2 within a Parkinson’s disease cohort 32 . Furthermore, rare mutations in SLC18A2 result in infantile Parkinsonism 33 – 35 .…”

Section: Discussionmentioning

confidence: 97%

Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson’s disease

Bucher

Barrett

Moon

et al. 2020

npj Parkinsons Dis.

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The catecholamine neurotransmitter dopamine has the potential to act as an endogenous neurotoxin when its vesicular sequestration is dysregulated. Despite postmortem analyses from patients with Parkinson’s disease that demonstrate decreased vesicular sequestration of dopamine with a corresponding increase in dopamine metabolism, dopamine’s contribution to nigrostriatal dopaminergic degeneration in Parkinson’s disease has been debated. Here, we present a new in vivo model demonstrating the induction of Parkinson’s disease-associated pathogenic mechanisms of degeneration resulting from acquired dysregulation of dopamine sequestration in nigrostriatal dopaminergic neurons in adult rats. Utilizing adeno-associated virus (serotype 2), viral-mediated small-hairpin RNA interference of endogenous vesicular monoamine transporter 2 (VMAT2) expression resulted in a loss of VMAT2 protein expression in transduced dopaminergic cell bodies in the substantia nigra with a corresponding loss of VMAT2 protein within the striatal terminals. The loss of VMAT2 resulted in an accumulation of cytosolic dopamine and subsequent increased dopamine metabolism, deficits in dopamine-mediated behaviors, and degeneration of nigrostriatal dopaminergic neurons that was rescued through reintroduction of exogenous VMAT2, demonstrating that the toxicity was specific to the loss of VMAT2. Analysis of parkinsonian pathogenic mechanisms of degeneration identified oxidative damage, activation of Parkinson’s disease-associated kinase LRRK2, and the formation of aberrant α-synuclein. This model demonstrates that a progressive acquired loss of VMAT2 expression in adulthood is sufficient to induce Parkinson’s disease-associated pathogenic mechanisms of degeneration and provides a new model to further investigate the consequences of cytosolic dopamine.

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Section: Discussionmentioning

confidence: 97%

Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson’s disease

Bucher

Barrett

Moon

et al. 2020

npj Parkinsons Dis.

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“…Decreases both in the amount and activity of VMAT2 have been detected in postmortem tissue from PD patients, , and mutations in VMAT2 have been identified as causative of infantile parkinsonism . Recent work has identified low-activity variants in VMAT2 that may increase the risk of PD, and gain of function polymorphisms in SLC18A2 have been associated with a decreased risk for PD. − Furthermore, data shows a decrease in VMAT2 mRNA from platelets of PD patients, suggesting that a systemic deficiency in VMAT2 may be a pathologic characteristic of the disease . Genetic predisposition only accounts for a portion of PD risk, the rest of which is explained by environmental exposures including manganese and the pesticides rotenone and dieldrin. − While the mechanisms by which these toxicants contribute to PD pathogenesis remain unknown, it is possible that these toxicants exert their neurotoxicity in part by affecting VMAT2 function. , …”

Section: Introductionmentioning

confidence: 99%

Assessing Vesicular Monoamine Transport and Toxicity Using Fluorescent False Neurotransmitters

Black

Bucher

Bradner

et al. 2020

Chem. Res. Toxicol.

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Impairments in the vesicular packaging of dopamine result in an accumulation of dopamine in the cytosol. Cytosolic dopamine is vulnerable to two metabolic processesenzymatic catabolism and enzymatic-or auto-oxidationthat form toxic metabolites and generate reactive oxygen species. Alterations in the expression or activity of the vesicular monoamine transporter 2 (VMAT2), which transports monoamines such as dopamine from the cytosol into the synaptic vesicle, result in dysregulated dopamine packaging. Here, we developed a series of assays using the fluorescent false neurotransmitter 206 (FFN206) to visualize VMAT2-mediated vesicular packaging at baseline and following pharmacological and toxicological manipulations. As a proof of principle, we observed a significant reduction in vesicular FFN206 packaging after treatment with the VMAT2 inhibitors reserpine (IC 50 : 73.1 nM), tetrabenazine (IC 50 : 30.4 nM), methamphetamine (IC 50 : 2.4 μM), and methylphenidate (IC 50 : 94.3 μM). We then applied the assay to investigate the consequences on vesicular packaging by environmental toxicants including the pesticides paraquat, rotenone, and chlorpyrifos, as well as the halogenated compounds unichlor, perfluorooctanesulfonic acid, Paroil, Aroclor 1260, and hexabromocyclododecane. Several of the environmental toxicants showed minor impairment of the vesicular FFN206 loading, suggesting that the toxicants are weak VMAT2 inhibitors at the concentrations tested. The assay presented here can be applied to investigate the effect of additional pharmacological compounds and environmental toxicants on vesicular function, which will provide insight into how exposures to such factors are involved in the pathogenesis of monoaminergic diseases such as Parkinson's disease, and the assay can be used to identify pharmacological agents that influence VMAT2 activity.

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“…The catecholamine functional abnormalities reported here render the model suitable for testing interventional strategies that might salvage dysfunctional catecholaminergic neurons. This understanding might lead to novel disease-modifying treatments, such as enhancing VMAT or ALDH activity ( Lohr and Miller, 2014 ; Xiong et al, 2016 ; Chiu et al, 2015 ), or to combined strategies for which this model is useful. We believe that, in the future, combination pharmacotherapy will prove to be effective for neurodegenerative diseases just as in other areas of medicine.…”

Section: Discussionmentioning

confidence: 99%

The rat rotenone model reproduces the abnormal pattern of central catecholamine metabolism found in Parkinson's disease

Landau

Halperin

Sullivan

et al. 2022

Disease Models &Amp; Mechanisms

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Background: Recent reports indicate that Parkinson's disease (PD) involves specific functional abnormalities in residual neurons—decreased vesicular sequestration of cytoplasmic catecholamines via the vesicular monoamine transporter (VMAT) and decreased aldehyde dehydrogenase (ALDH) activity. This double hit builds up the autotoxic metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the focus of the catecholaldehyde hypothesis for the pathogenesis of PD. An animal model is needed that reproduces this abnormal catecholamine neurochemical pattern. Methods: Adult rats received subcutaneous vehicle or rotenone (2 mg/kg/day via a minipump) for 10 days. Locomotor activity was recorded and striatal tissue sampled for catechol contents and catechol ratios that indicate the above abnormalities. Results: Compared to vehicle, rotenone reduced locomotor activity (p=0.002), decreased tissue dopamine concentrations (p=0.00001), reduced indices of vesicular sequestration (3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine) and ALDH activity (DOPAC/DOPAL) (p=0.0025, p=0.036), and increased DOPAL levels (p=0.04). Conclusions: The rat rotenone model involves functional abnormalities in catecholaminergic neurons that replicate the pattern found in PD putamen. These include a vesicular storage defect, decreased ALDH activity, and DOPAL buildup. The rat rotenone model provides a suitable in vivo platform for studying the catecholaldehyde hypothesis.

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hVMAT2: A Target of Individualized Medication for Parkinson's Disease

Cited by 13 publications

References 60 publications

Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson’s disease

Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson’s disease

Assessing Vesicular Monoamine Transport and Toxicity Using Fluorescent False Neurotransmitters

The rat rotenone model reproduces the abnormal pattern of central catecholamine metabolism found in Parkinson's disease

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