Altered vesicular dopamine storage in Parkinson's disease: a premature demise

Caudle, W. Michael; Colebrooke, Rebecca E.; Emson, Piers C.; Miller, Gary W.

doi:10.1016/j.tins.2008.02.010

Cited by 107 publications

(95 citation statements)

References 70 publications

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“…Subsequently, L-DOPA is then decarboxylated by AADC to yield DA. Cytosolic DA can then be either packaged into vesicles by VMAT 2 or metabolized by monoamine oxidase B (48,49). Both of these pathways would ensure the maintenance of low levels of cytosolic DA, minimizing its potential toxic effects.…”

Section: Discussionmentioning

confidence: 99%

A Biochemical and Functional Protein Complex Involving Dopamine Synthesis and Transport into Synaptic Vesicles

Cartier

Parra

Baust

et al. 2010

Journal of Biological Chemistry

115

103

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Synaptic transmission depends on neurotransmitter pools stored within vesicles that undergo regulated exocytosis. In the brain, the vesicular monoamine transporter-2 (VMAT 2 ) is responsible for the loading of dopamine (DA) and other monoamines into synaptic vesicles. Prior to storage within vesicles, DA synthesis occurs at the synaptic terminal in a two-step enzymatic process. First, the rate-limiting enzyme tyrosine hydroxylase (TH) converts tyrosine to di-OH-phenylalanine. Aromatic amino acid decarboxylase (AADC) then converts di-OH-phenylalanine into DA. Here, we provide evidence that VMAT 2 physically and functionally interacts with the enzymes responsible for DA synthesis. In rat striata, TH and AADC co-immunoprecipitate with VMAT 2 , whereas in PC 12 cells, TH co-immunoprecipitates with the closely related VMAT 1 and with overexpressed VMAT 2 . GST pull-down assays further identified three cytosolic domains of VMAT 2 involved in the interaction with TH and AADC. Furthermore, in vitro binding assays demonstrated that TH directly interacts with VMAT 2 . Additionally, using fractionation and immunoisolation approaches, we demonstrate that TH and AADC associate with VMAT 2 -containing synaptic vesicles from rat brain. These vesicles exhibited specific TH activity. Finally, the coupling between synthesis and transport of DA into vesicles was impaired in the presence of fragments involved in the VMAT 2 /TH/AADC interaction. Taken together, our results indicate that DA synthesis can occur at the synaptic vesicle membrane, where it is physically and functionally coupled to VMAT 2 -mediated transport into vesicles.Monoamines, including dopamine (DA), 3 norepinephrine (NE), and serotonin (5-HT), are neurotransmitters that play major roles in a variety of brain functions, including emotion, reward, cognition, memory, attention, locomotion, and stress control (1-6). In neurons and neuroendocrine cells, monoamines are stored in large dense core vesicles (LDCVs) and small synaptic vesicles (SVs) (7-11) that undergo regulated exocytosis through a complex network of protein-protein interactions (12). Loading of monoamines into LDCVs and SVs of neurons and neuroendocrine cells is mediated by two vesicular monoamine transporter isoforms: VMAT 1 (13) and VMAT 2 (14). These transporters contain 12 putative transmembrane domains with both the N and C termini facing the cytosolic side of the vesicle membrane. VMAT 1 is mostly present in LDCVs of neuroendocrine cells, including chromaffin and PC12 cells, whereas VMAT 2 is primarily expressed by monoaminergic neurons of the central nervous system (15). In midbrain DA neurons, VMAT 2 is sorted to LDCVs and SVs in axon terminals and to LDCVs and tubulo-vesicular structures in the somatodendritic compartment (7)(8)(9)(10)(11)15).It is generally accepted that VMAT 2 transports DA that has been previously synthesized in the cytosolic compartment of the presynaptic terminal (16). DA synthesis requires two enzymatic reactions. First, tyrosine hydroxylase (TH) converts tyrosine into DOP...

show abstract

Section: Discussionmentioning

confidence: 99%

A Biochemical and Functional Protein Complex Involving Dopamine Synthesis and Transport into Synaptic Vesicles

Cartier

Parra

Baust

et al. 2010

Journal of Biological Chemistry

115

103

View full text Add to dashboard Cite

show abstract

“…Differences between genotypes were compared by two-tailed t tests, except where indicated. One-tailed t tests, assuming increases in the VMAT2-HI mice, were used in analyses where lower VMAT2 function has previously been shown to result in reduced outcomes (e.g., HPLC) (17,23). Stereological counts and densitometric analysis were analyzed using two-way ANOVA (with treatment and genotype as factors) with Bonferroni post hoc tests.…”

Section: Methodsmentioning

confidence: 99%

“…VMAT2 is also essential for survival of dopamine neurons as cytosolic dopamine is neurotoxic (11,12). By sequestering intracellular dopamine into vesicles, VMAT2 prevents cytosolic dopamine accumulation and its subsequent conversion to neurotoxic species (13)(14)(15)(16)(17). Thus, VMAT2 serves two primary functions: to mediate monoamine neurotransmission and to counteract intracellular toxicity.…”

mentioning

confidence: 99%

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

Lohr¹,

Bernstein²,

Stout³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

175

171

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Significance Several therapeutic strategies have been used to enhance monoamine neurotransmitter signaling. However, many of these interventions have deleterious side effects or lose effectiveness due to off-target actions and system feedback. These undesirable consequences likely occur because of temporal dysregulation of neurotransmitter release and uptake. We demonstrate that increasing vesicular packaging enhances dopamine neurotransmission without this signaling disruption. Mice with elevated vesicular monoamine transporter display increased dopamine release, improved outcomes on anxiety and depressive behaviors, enhanced locomotion, and protection from a Parkinson disease-related neurotoxic insult. The malleable nature of the dopamine vesicle suggests that interventions aimed at enhancing vesicle filling may be of therapeutic benefit.

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“…Once formed, dopamineis safely stored in high millimolar concentrations in synaptic vesicles following uptake by VMAT2 [118]. Impairment of vesicular storage of dopamine, which may be due to the presence of alphaͲsyn protofibrils, oxidative stress or weak base compounds such as methamphetamine(further describedbelow) [119], leads to increased dopaminelevels in the cytoplasm. Concordantly, alphaͲsyn overexpression was shown to increase cytosolic catecholamine concentration [120].…”

Section: Dopamine and Oxidative Stressmentioning

confidence: 98%

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2012

Free Radical Biology and Medicine

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Altered vesicular dopamine storage in Parkinson's disease: a premature demise

Cited by 107 publications

References 70 publications

A Biochemical and Functional Protein Complex Involving Dopamine Synthesis and Transport into Synaptic Vesicles

A Biochemical and Functional Protein Complex Involving Dopamine Synthesis and Transport into Synaptic Vesicles

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

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