HOT
TOPICS
VMAT2 and Parkinson’s Disease: Old Dog, New Tricks Lohr KM, Bernstein AI, Stout KA, et al. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo. Proc Natl Acad Sci U S A 2014 Jun 16. pii: 201402134. [Epub ahead of print] PubMed PMID: 24979780.
The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles by the vesicular monoamine transporter (VMAT2), which protects against DA metabolic degradation and associated toxicity. Indeed, defects in cytosolic handling of DA increase levels of DA-generated oxy- radicals, ultimately resulting in the degeneration of DAergic neurons.1 Thus, VMAT2 serves to mediate monoamine neurotransmission and to counteract intracellular toxicity. Previous data clearly show that disruption of VMAT2 function produces adverse effects.2,3 Similarly, a VMAT2 mutation in humans that dramatically reduces vesicular function was recently linked to an infantile parkinson-like condition with symptoms caused by deficits in all monoamines.4 Moreover, recently, Pifl and coworkers5 provided data from brains of PD patients and 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) monkeys indicating that VMAT2 defects may be an early abnormality leading to nigrostriatal DA neuronal death in PD.5 Now, Lohr et al. have generated a transgenic mouse with increased levels of VMAT2 via a bacterial artificial chromosome and found that such elevation led to increased striatal dopamine content, as measured by high-pressure liquid chromatography, and in dopamine release from striatal slices, as measured by fast-scan cyclic voltammetry. Stereological counts of nigral tyrosine hydroxylase-positive (TH1) neurons showed that this enhanced dopamine content was not caused by an increase in the number of midbrain neurons. Using measurements from immunogold electron micrographs from TH1 terminals in the striatum, they showed that the average vesicle volume in VMAT2 transgenic mice was higher than that in wild-type mice. Unexpectedly, this increased dopamine signaling did not result in anxiety or in manic-like behaviors typically associated with hyperdopaminergic states. In fact, using the marble-burying assay and the forced-swim test, the authors found improved outcomes on anxiety and depressive behaviors and increased movement. Although these results imply an involvement of additional monoamine neurotransmitters
such as serotonin or norepinephrine, these findings suggest that elevated VMAT2 function in vivo may have benefits in altering mood and affective behaviors. Additionally, the authors found the genotype conferred protection from MPTP, as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. Several therapeutic strategies have been used to enhance monoamine neurotransmitter signaling. Usually, these interventions have deleterious side effects because of the temporal dysregulation of neurotransmitter release and uptake. The study described by Lohr and colleagues suggests that enhanced monoaminergic vesicular filling can be sustained over time without signaling disruption. Furthermore, this enhanced vesicular filling may provide novel targets for neuroprotective therapies for a variety of central nervous system disorders that involve the storage and release of dopamine, serotonin, or norepinephrine. Javier Blesa, PhD Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA
References 1.
Mosharov EV, Larsen KE, Kanter E, et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 2009;62:218-229. doi: 10.1016/j.neuron.2009.01.033.
2.
Kirshner N. Uptake of catecholamines by a particulate fraction of the adrenal medulla. Science 1962;135:107-108.
3.
Fon EA, Pothos EN, Sun BC, Killeen N, Sulzer D, Edwards RH. Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 1997;19:12711283.
4.
Rilstone JJ, Alkhater RA, Minassian BA. Brain dopamineserotonin vesicular transport disease and its treatment. N Engl J Med 2013;368:543-550.
5.
Pifl C, Rajput A, Reither H, et al. Is Parkinson’s disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum. J Neurosci 2014;34:8210-8218.
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Relevant conflicts of interest/financial disclosures: Nothing to report. Received: 6 July 2014; Accepted: 14 July 2014 Published online 14 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25986
Movement Disorders, Vol. 29, No. 10, 2014
1241
TOPICS
VMAT2 and Parkinson’s Disease: Old Dog, New Tricks Lohr KM, Bernstein AI, Stout KA, et al. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo. Proc Natl Acad Sci U S A 2014 Jun 16. pii: 201402134. [Epub ahead of print] PubMed PMID: 24979780.
The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles by the vesicular monoamine transporter (VMAT2), which protects against DA metabolic degradation and associated toxicity. Indeed, defects in cytosolic handling of DA increase levels of DA-generated oxy- radicals, ultimately resulting in the degeneration of DAergic neurons.1 Thus, VMAT2 serves to mediate monoamine neurotransmission and to counteract intracellular toxicity. Previous data clearly show that disruption of VMAT2 function produces adverse effects.2,3 Similarly, a VMAT2 mutation in humans that dramatically reduces vesicular function was recently linked to an infantile parkinson-like condition with symptoms caused by deficits in all monoamines.4 Moreover, recently, Pifl and coworkers5 provided data from brains of PD patients and 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) monkeys indicating that VMAT2 defects may be an early abnormality leading to nigrostriatal DA neuronal death in PD.5 Now, Lohr et al. have generated a transgenic mouse with increased levels of VMAT2 via a bacterial artificial chromosome and found that such elevation led to increased striatal dopamine content, as measured by high-pressure liquid chromatography, and in dopamine release from striatal slices, as measured by fast-scan cyclic voltammetry. Stereological counts of nigral tyrosine hydroxylase-positive (TH1) neurons showed that this enhanced dopamine content was not caused by an increase in the number of midbrain neurons. Using measurements from immunogold electron micrographs from TH1 terminals in the striatum, they showed that the average vesicle volume in VMAT2 transgenic mice was higher than that in wild-type mice. Unexpectedly, this increased dopamine signaling did not result in anxiety or in manic-like behaviors typically associated with hyperdopaminergic states. In fact, using the marble-burying assay and the forced-swim test, the authors found improved outcomes on anxiety and depressive behaviors and increased movement. Although these results imply an involvement of additional monoamine neurotransmitters
such as serotonin or norepinephrine, these findings suggest that elevated VMAT2 function in vivo may have benefits in altering mood and affective behaviors. Additionally, the authors found the genotype conferred protection from MPTP, as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. Several therapeutic strategies have been used to enhance monoamine neurotransmitter signaling. Usually, these interventions have deleterious side effects because of the temporal dysregulation of neurotransmitter release and uptake. The study described by Lohr and colleagues suggests that enhanced monoaminergic vesicular filling can be sustained over time without signaling disruption. Furthermore, this enhanced vesicular filling may provide novel targets for neuroprotective therapies for a variety of central nervous system disorders that involve the storage and release of dopamine, serotonin, or norepinephrine. Javier Blesa, PhD Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA
References 1.
Mosharov EV, Larsen KE, Kanter E, et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 2009;62:218-229. doi: 10.1016/j.neuron.2009.01.033.
2.
Kirshner N. Uptake of catecholamines by a particulate fraction of the adrenal medulla. Science 1962;135:107-108.
3.
Fon EA, Pothos EN, Sun BC, Killeen N, Sulzer D, Edwards RH. Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 1997;19:12711283.
4.
Rilstone JJ, Alkhater RA, Minassian BA. Brain dopamineserotonin vesicular transport disease and its treatment. N Engl J Med 2013;368:543-550.
5.
Pifl C, Rajput A, Reither H, et al. Is Parkinson’s disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum. J Neurosci 2014;34:8210-8218.
------------------------------------------------------------
Relevant conflicts of interest/financial disclosures: Nothing to report. Received: 6 July 2014; Accepted: 14 July 2014 Published online 14 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25986
Movement Disorders, Vol. 29, No. 10, 2014
1241
