VMAT2-Deficient Mice Display Nigral and Extranigral Pathology and Motor and Nonmotor Symptoms of Parkinson's Disease

Dopamine is transported into synaptic vesicles by the vesicular monoamine transporter (VMAT2; SLC18A2). Disruption of dopamine storage has been hypothesized to damage the dopamine neurons that are lost in Parkinson's disease. By disrupting vesicular storage of dopamine and other monoamines, we have created a progressive mouse model of PD that exhibits catecholamine neuron loss in the substantia nigra pars compacta and locus coeruleus and motor and nonmotor symptoms. With a 95% reduction in VMAT2 expression, VMAT2-deficient animals have decreased motor function, progressive deficits in olfactory discrimination, shorter latency to behavioral signs of sleep, delayed gastric emptying, anxiety-like behaviors at younger ages, and a progressive depressive-like phenotype. Pathologically, the VMAT2-deficient mice display progressive neurodegeneration in the substantia nigra (SNpc), locus coeruleus (LC), and dorsal raphe (DR) coupled with α-synuclein accumulation. Taken together, these studies demonstrate that reduced vesicular storage of monoamines and the resulting disruption of the cytosolic environment may play a role in the pathogenesis of parkinsonian symptoms and neurodegeneration. The multisystem nature of the VMAT2-deficient mice may be useful in developing therapeutic strategies that go beyond the dopamine system.

• Publication year

  2011

• Venue

  Parkinson's Disease

• Publication date

  2011-02-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.4061/2011/124165PMID 21403896PMCID 3043293
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Neurodegeneration and neuroprotection in Parkinson disease

  2011influential reference
• Nonmotor Symptoms of Parkinson's Disease Revealed in an Animal Model with Reduced Monoamine Storage Capacity

  2009influential reference
• Oxidative Stress in Parkinson's Disease

  2008cited by this paper
• Inhibition of vesicular monoamine transporter-2 activity in alpha-synuclein stably transfected SH-SY5Y cells.

  2008cited by this paper
• Reduced Vesicular Storage of Dopamine Causes Progressive Nigrostriatal Neurodegeneration

  2007influential reference
• Inhibition of Vesicular Monoamine Transporter-2 Activity in α-Synuclein Stably Transfected SH-SY5Y Cells

  2007cited by this paper
• Norepinephrine: The redheaded stepchild of Parkinson's disease.

  2007influential reference
• Vmat2 Heterozygous Mutant Mice Display a Depressive-Like Phenotype

  2007influential reference
• Olfactory Dysfunction in Parkinson’s Disease

  2007cited by this paper
• Differential gene expression in the striatum of mice with very low expression of the vesicular monoamine transporter type 2 gene.

  2007cited by this paper
• Non-motor dysfunction in Parkinson's disease.

  2007cited by this paper
• Increased vulnerability to l-DOPA toxicity in dopaminergic neurons from VMAT2 heterozygote knockout mice

  2007cited by this paper
• Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

  2006cited by this paper
• Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women.

  2006cited by this paper
• Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease

  2006influential reference
• α-Synuclein Overexpression Increases Cytosolic Catecholamine Concentration

  2006cited by this paper
• The parkinson's complex: Parkinsonism is just the tip of the iceberg

  2006cited by this paper
• The pathogenesis of cell death in Parkinson's disease

  2006cited by this paper
• Reversible Inhibition of α-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations*

  2005cited by this paper
• Dbh(-/-) mice are hypotensive, have altered circadian rhythms, and have abnormal responses to dieting and stress.

  2004cited by this paper
• Depression and Parkinson’s disease

  2004cited by this paper
• The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine

  2004cited by this paper
• Structural conservation in the major facilitator superfamily as revealed by comparative modeling

  2004cited by this paper
• Neurodegeneration and neuroprotection in Parkinson disease

  2004cited by this paper
• [Etiology and pathogenesis of Parkinson's disease: from mitochondrial dysfunctions to familial Parkinson's disease].

  2004cited by this paper
• Neurodegeneration und Neuroprotektion

  2004cited by this paper
• Staging of brain pathology related to sporadic Parkinson's disease.

  2003cited by this paper
• Parkinson's Disease Mechanisms and Models

  2003influential reference
• Oxidative stress in Parkinson's disease

  2003cited by this paper
• Presynaptic control of striatal dopamine neurotransmission in adult vesicular monoamine transporter 2 (VMAT2) mutant mice

  2003influential reference
• Concomitant development of oral dyskinesia and memory deficits in reserpine-treated male and female mice.

  2002cited by this paper
• Evaluation of the face validity of reserpine administration as an animal model of depression--Parkinson's disease association.

  2002cited by this paper
• A simple method to measure stride length as an index of nigrostriatal dysfunction in mice.

  2002cited by this paper
• Detection of behavioral impairments correlated to neurochemical deficits in mice treated with moderate doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

  2002cited by this paper
• Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages)

  2002cited by this paper
• L-DOPA does not cause neurotoxicity in VMAT2 heterozygote knockout mice.

  2002cited by this paper
• Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein.

  2002influential reference
• Kinetic Stabilization of the α-Synuclein Protofibril by a Dopamine-α-Synuclein Adduct

  2001cited by this paper
• Mice with Very Low Expression of the Vesicular Monoamine Transporter 2 Gene Survive into Adulthood: Potential Mouse Model for Parkinsonism

  2001influential reference
• Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice

  2001cited by this paper
• Autosomal recessive juvenile parkinsonism.

  2000cited by this paper
• Etiology and pathogenesis of Parkinson's disease.

  1999cited by this paper
• Dopamine transporters and neuronal injury.

  1999influential reference
• Increased Methamphetamine Neurotoxicity in Heterozygous Vesicular Monoamine Transporter 2 Knock-Out Mice

  1999influential reference
• Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson's disease.

  1999cited by this paper
• Hypothesis: The role of dopaminergic transporters in selective vulnerability of cells in Parkinson's disease

  1998cited by this paper
• Iodine-123-N-ω-Fluoropropyl-2β-Carbomethoxy-3β-(4-Iodophenyl)Tropane SPECT in Healthy Controls and Early-Stage, Drug-Naive Parkinson's Disease

  1998cited by this paper
• Iodine-123-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iod ophenyl)tropane SPECT in healthy controls and early-stage, drug-naive Parkinson's disease.

  1998cited by this paper
• Increased MPTP Neurotoxicity in Vesicular Monoamine Transporter 2 Heterozygote Knockout Mice

  1998cited by this paper
• The role of vesicular transport proteins in synaptic transmission and neural degeneration.

  1997cited by this paper
• Symptoms and duration of the prodromal phase in parkinson's disease

  1997cited by this paper
• Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine.

  1997cited by this paper
• VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity.

  1997influential reference
• Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action.

  1997cited by this paper
• Vesicular neurotransmitter transporters: from bacteria to humans.

  1995cited by this paper
• The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors.

  1994cited by this paper
• A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs

  1993cited by this paper
• In Vivo Imaging of Vesicular Monoamine Transporters in Human Brain Using [11C]Tetrabenazine and Positron Emission Tomography

  1993cited by this paper
• A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter.

  1992cited by this paper
• Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson's disease.

  1992cited by this paper
• Expression cloning of a reserpine-sensitive vesicular monoamine transporter.

  1992cited by this paper
• New developments in the pathology of Parkinson's disease.

  1990cited by this paper
• Structure and function of vacuolar class of ATP-driven proton pumps.

  1989cited by this paper
• ATP-driven H+ pumping into intracellular organelles.

  1986cited by this paper
• Olfactory impairment in Parkinson's disease

  1983cited by this paper
• Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones.

  1978cited by this paper
• Mental depression in hypertensive patients treated for long periods with large doses of reserpine.

  1954cited by this paper
• Reserpine Antagonism of Morphine Analgesia in Mice

  1954cited by this paper
• An Essay on the Shaking Palsy

  1817influential reference

• Osmotin-derived 9-amino-acid peptide alleviates α-synuclein and MPTP-induced glial cell activation mediated neuroinflammation, protecting dopaminergic neurons in Parkinson’s disease mice brain

  2026cites this paper
• Evaluation of the Relationship between Vesicular Monoamine Transporter 2 (VMAT2) Inhibition and Neurologic Adverse Events in Approved Drugs.

  2025cites this paper
• Redefining dopaminergic synapses beyond the classical paradigm.

  2025cites this paper
• Age-dependent impairment of dopamine D1 receptor signalling in mouse striatum by FMR1 variant P626L

  2025cites this paper
• Short-Term High-Fat Diet Elevates Oxidative Stress in Male but Not Female A53T mice Without Altering Striatal Dopaminergic Markers.

  2025cites this paper
• Leveraging animal models to understand non-motor symptoms of Parkinson's disease.

  2025cites this paper
• Investigating affective neuropsychiatric symptoms in rodent models of Parkinson's disease.

  2024cites this paper
• Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)‐[11C]YH132: Application in Drug Development and Neurodegenerative Diseases

  2024cites this paper
• The BE (2)-M17 neuroblastoma cell line: revealing its potential as a cellular model for Parkinson’s disease

  2024cites this paper
• Experimental models of Parkinson's disease: Challenges and Opportunities.

  2024cites this paper
• Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology.

  2024cites this paper
• Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity

  2024cites this paper
• N-acetylcysteine increases dopamine release and prevents the deleterious effects of 6-OHDA on the expression of VMAT2, α-synuclein, and tyrosine hydroxylase

  2024cites this paper
• Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s disease

  2023cites this paper
• Vesicular monoamine transporter (VMAT) regional expression and roles in pathological conditions

  2023cites this paper
• Effect of altered production and storage of dopamine on development and behavior in C. elegans

  2023cites this paper
• Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson’s Disease

  2023cites this paper
• Altered DNA repair related proteins in Parkinson’s disease model VMAT2 Lo mice

  2023cites this paper
• Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity

  2023cites this paper
• Developmental exposure to the Parkinson’s disease-associated organochlorine pesticide dieldrin alters dopamine neurotransmission in α-synuclein pre-formed fibril (PFF)-injected mice

  2023cites this paper
• Identification of Hub Genes and Potential Molecular Pathogenesis in Substantia Nigra in Parkinson's Disease via Bioinformatics Analysis

  2023cites this paper
• Sleep and circadian rhythms in α‐synucleinopathies—Perspectives for disease modification

  2023cites this paper
• Upregulated DNA Damage-Linked Biomarkers in Parkinson's Disease Model Mice

  2023cites this paper
• Motility phenotype in a zebrafish vmat2 mutant

  2022cites this paper
• Dopamine Transporter, PhosphoSerine129 α-Synuclein and α-Synuclein Levels in Aged LRRK2 G2019S Knock-In and Knock-Out Mice

  2022cites this paper
• Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and neurodegeneration with brain iron accumulation disorders.

  2022cites this paper
• Psychiatric Disorders in Animal Models of Depression

  2021cites this paper
• Dopamine Homeostasis and Role of VMAT2 in Neurodegeneration

  2021cites this paper
• In vitro inhibition of glutathione-S-transferase by dopamine and its metabolites, 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylacetic acid.

  2021cites this paper
• Further Characterization of Intrastriatal Lipopolysaccharide Model of Parkinson’s Disease in C57BL/6 Mice

  2021cites this paper
• Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

  2021cites this paper
• Protective effects of intracerebroventricular adiponectin against olfactory impairments in an amyloid β1–42 rat model

  2021cites this paper
• Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson’s disease

  2021influential citation
• Alterations of the Motor and Olfactory Functions Related to Parkinson’s Disease in Transgenic Mice With a VMAT2-Deficiency in Dopaminergic Neurons

  2020cites this paper
• Vesicular monoamine transporter 2 mediates fear behavior in mice

  2020cites this paper
• Assessing Vesicular Monoamine Transport and Toxicity Using Fluorescent False Neurotransmitters.

  2020cites this paper
• Genetic or toxicant induced disruption of vesicular monoamine storage and global metabolic profiling in Caenorhabditis elegans

  2020cites this paper
• Improved functional and histochemical outcomes in l-DOPA plus tolcapone treated VMAT2-deficient mice.

  2020cites this paper
• Diabetes Causes Dysfunctional Dopamine Neurotransmission Favoring Nigrostriatal Degeneration in Mice

  2020cites this paper
• EIn vivo modeling of prodromal stage of Parkinson's disease.

  2020cites this paper
• Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits

  2020cites this paper
• Reciprocal interaction between monoaminergic systems and the pedunculopontine nucleus: Implication in the mechanism of L-DOPA.

  2019cites this paper
• Presynaptic regulation of dopamine release: Role of the DAT and VMAT2 transporters

  2019cites this paper
• Reduced VMAT2 expression exacerbates the hyposmia in the MPTP model of Parkinson's disease.

  2019cites this paper
• Critical Role of Oxidatively Damaged DNA in Selective Noradrenergic Vulnerability.

  2019cites this paper
• Olfaction, among the First Senses to Develop and Decline

  2018cites this paper
• Membrane cholesterol removal and replenishment affect rat and monkey brain monoamine transporters

  2018cites this paper
• What have we learned recently from transgenic mouse models about neurodegeneration? The most promising discoveries of this millennium

  2018cites this paper
• Can Interactions Between α-Synuclein, Dopamine and Calcium Explain Selective Neurodegeneration in Parkinson's Disease?

  2018cites this paper
• Synthesis and preliminary evaluation of 131I-9-iodovinyl-tetrabenazine targeting vesicular monoamine transporter 2

  2018cites this paper
• Tyrosine Hydroxylase, Vesicular Monoamine Transporter and Dopamine Transporter mRNA Expression in Nigrostriatal Tissue of Rats with Pedunculopontine Neurotoxic Lesion

  2018cites this paper
• Immunochemical localization of vesicular monoamine transporter 2 (VMAT2) in mouse brain.

  2017cites this paper
• Alpha-synuclein, epigenetics, mitochondria, metabolism, calcium traffic, & circadian dysfunction in Parkinson's disease. An integrated strategy for management.

  2017cites this paper
• Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease

  2017cites this paper
• Autoimmune Aspects of Neurodegenerative and Psychiatric Diseases: A Template for Innovative Therapy

  2017cites this paper
• Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice

  2017cites this paper
• Parkinson’s disease: experimental models and reality

  2017cites this paper
• Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease

  2017cites this paper
• Spontaneously Hypertensive Rats (SHR) Are Resistant to a Reserpine-Induced Progressive Model of Parkinson’s Disease: Differences in Motor Behavior, Tyrosine Hydroxylase and α-Synuclein Expression

  2017cites this paper
• Characterization of Vesicular Monoamine Transporter 2 and its role in Parkinson's Disease Pathogenesis using Drosophila

  2016cites this paper
• Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

  2016cites this paper
• Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease

  2016cites this paper
• Circadian regulation and its disorders in Parkinson’s disease patients. Part 2: Experimental models, alpha-synuclein, and melatonin

  2016cites this paper
• Vesicular Monoamine Transporter 2 (VMAT2) Level Regulates MPTP Vulnerability and Clearance of Excess Dopamine in Mouse Striatal Terminals.

  2016cites this paper
• Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour.

  2016cites this paper
• Novel MRI Approaches to the Detection and Evaluation of Neurodegenerative Disease

  2015cites this paper
• Modulation of the expression and function of dopaminergic presynaptic proteins by the statins : Potential implication for the therapeutic intervention in Parkinson’s disease.

  2015cites this paper
• Circadian Dysfunction in Parkinson's Disease

  2015cites this paper
• JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death.

  2015cites this paper
• Inhibiting COMT in a mouse model of Parkinson's disease: a trial of Tolcapone in VMAT2-deficient mice

  2015influential citation
• In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra.

  2015cites this paper
• Polymorphism in the Vesicular Monoamine Transporter 2 Gene Decreases the Risk of Parkinson's Disease in Han Chinese Men

  2015cites this paper
• Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine.

  2015cites this paper
• Differential protein expression in the nucleus accumbens of high and low active mice.

  2015cites this paper
• Mutation in VMAT2 Causing a Pediatric Neurotransmitter Disease

  2015cites this paper
• Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus.

  2014cites this paper
• Regulation of DA Homeostasis and Role of VMAT2 in DA-Induced Neurodegeneration

  2014cites this paper
• The Role Of Sertonin And Vesicular Monoamine Transporters In The Adverse Responses To Methylenedioxymethamphetamine

  2014influential citation
• Parkinson’s disease: animal models and dopaminergic cell vulnerability

  2014cites this paper
• Premotor parkinsonism models.

  2014cites this paper
• Olfactory Assays for Mouse Models of Neurodegenerative Disease

  2014cites this paper
• Monoamine transporters

  2013influential citation
• VMAT1 deletion causes neuronal loss in the hippocampus and neurocognitive deficits in spatial discrimination.

  2013cites this paper
• Circadian dysfunction may be a key component of the non-motor symptoms of Parkinson's disease: insights from a transgenic mouse model.

  2013cites this paper
• AGC1‐malate aspartate shuttle activity is critical for dopamine handling in the nigrostriatal pathway

  2013influential citation
• Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

  2013cites this paper
• Vivo-Morpholinos Induced Transient Knockdown of Physical Activity Related Proteins

  2013influential citation
• Mitochondrial dysfunction and oxidative stress in Parkinson's disease and monogenic parkinsonism.

  2013cites this paper
• A phenotypic model recapitulating the neuropathology of Parkinson's disease

  2013cites this paper
• Skeletal Muscle as a Mechanism for Peripheral Regulation of Voluntary Physical Activity

  2013cites this paper
• Analysis of vesicular monoamine transporter 2 polymorphisms in Parkinson’s disease

  2013cites this paper
• Telmisartan attenuates MPTP induced dopaminergic degeneration and motor dysfunction through regulation of α-synuclein and neurotrophic factors (BDNF and GDNF) expression in C57BL/6J mice.

  2013cites this paper
• Functional genetic variants in the vesicular monoamine transporter 1 (VMAT1) modulate emotion processing

  2012cites this paper
• Overexpression of VMAT-2 and DT-diaphorase protects substantia nigra-derived cells against aminochrome neurotoxicity.

  2012cites this paper
• PET Imaging a MPTP-Induced Mouse Model of Parkinson’s Disease Using the Fluoropropyl-Dihydrotetrabenazine Analog [18F]-DTBZ (AV-133)

  2012cites this paper
• Covalent modification and inhibition of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, an endogenously produced neurotoxin relevant to Parkinson's disease

  2012cites this paper
• Catechol and aldehyde moieties of 3,4-dihydroxyphenylacetaldehyde contribute to tyrosine hydroxylase inhibition and neurotoxicity.

  2012cites this paper
• Mechanisms of dopamine quantal size regulation.

  2012cites this paper
• A fluorescent-based assay for live cell, spatially resolved assessment of vesicular monoamine transporter 2-mediated neurotransmitter transport.

  2012cites this paper
• Tracking extranigral degeneration in animal models of Parkinson’s disease: quest for effective therapeutic strategies

  2011cites this paper