DeCure for Brain dopamine-serotonin vesicular transport disease
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for brain dopamine-serotonin vesicular transport disease — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleBrain dopamine-serotonin vesicular transport disease maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for brain dopamine-serotonin vesicular transport disease is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
solute carrier family 18 member A2 (SLC18A2) — SLC18A2 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet ldpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8WRE · 2.9 Å · ligand L-DOPAMINE (LDP). Experimental structure, not a prediction.
What the evidence adds up to
In 2019 a child born of consanguineous parents presented with hypotonia, mental disability, epilepsy, uncontrolled movements, and gastrointestinal problems. A trial of L-DOPA was unsuccessful. Platelet studies revealed dysmorphic dense granules almost completely depleted of serotonin, and whole genome sequencing identified a novel homozygous p.P316A missense variant in SLC18A2, the gene coding for vesicular monoamine transporter 2 (VMAT2). The parents were heterozygous for the variant. This was the first report of defective platelet dense granule function linked to absent serotonin storage in a VMAT2-deficient patient without obvious clinical bleeding. The authors noted homology between serotonin metabolism in brain and platelets, suggesting platelets could serve as model cells for some neurological pathways.
Earlier work in Parkinson disease (PD) found reduced density of serotonin transporters in the striatum, measured by [11C](+)McN5652 PET in 13 patients versus 13 controls, with reductions in caudate and putamen (both P<.01) that correlated with disease stage. Striatal dopamine transporter binding was also reduced as expected. A 2014 review argued that altered vesicular storage of dopamine, mediated by VMAT2, may contribute to nigral neuron death in PD, citing human studies showing VMAT2 dysfunction in PD brain and transgenic mouse evidence of a reserve capacity that could be increased by enhancing VMAT2 function. The review proposed that drugs boosting VMAT2 activity might improve levodopa efficacy, increase dopamine transmission from remaining neurons, and protect against neurotoxic insults.
A 2007 SPECT study in eight healthy subjects given venlafaxine extended release (75 mg/d for 4 days then 150 mg/d for 5 days) found 55.4% inhibition of serotonin transporter binding in brainstem and 54.1% in diencephalon, while striatal dopamine transporter binding increased by 10.1%. The authors noted this pattern resembled that seen with the SSRI citalopram. A 1995 review described two gene families for monoamine transport: plasma membrane Na+/Cl--dependent carriers that terminate neurotransmitter action, and H+-dependent vesicular carriers that repackage monoamines for release. A 2016 overview of dopamine transporter mutant animals discussed their use in modelling neuropsychiatric disorders and identifying new therapeutic targets.
What remains missing is a specific clinical trial testing any VMAT2-enhancing drug in patients with the SLC18A2 missense variant, funding for such a trial, and any stratification of patients by genotype or platelet serotonin content. The single case report describes L-DOPA failure but no other drug attempts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Neurology · 2003 · 153 citations
Positron Emission Tomography of Striatal Serotonin Transporters in Parkinson Disease
AbstractBACKGROUND: Little is known about serotonin neurons in Parkinson disease (PD). OBJECTIVE: To study the serotonin system in PD with positron emission tomography, using the serotonin transporter radioligand [11C](+)McN5652. DESIGN AND PATIENTS: We measured the density of the serotonin transporter and the density of [11C]WIN35,428-labeled dopamine transporters in the striatum of 13 adults with PD and 13 age- and sex-matched controls. To assess the effects of possible differences in blood flow or brain atrophy, we also measured regional cerebral blood flow and the size of the regions of interest for the caudate nucleus and putamen. RESULTS: Patients with PD showed reductions in the specific distribution volumes of [11C](+)McN5652 in the caudate (P<.01) and putamen (P<.01), along with the expected reductions in striatal [11C]WIN35,428 binding (P<.01). There were no reductions in regional cerebral blood flow or the sizes of the regions of interest, mitigating against potential confounding effects of blood flow, brain atrophy, or partial volume effects. Reductions in serotonin transporter binding correlated with ratings of disease staging. CONCLUSIONS: These results suggest that the density of serotonin transporters, like that of dopamine transporters, is reduced in the striatum of patients with PD and that these changes are related to disease stage.
Journal of Neurogenetics · 2016 · 81 citations · open access
Dopamine transporter mutant animals: a translational perspective
AbstractThe dopamine transporter (DAT) plays an important homeostatic role in the control of both the extracellular and intraneuronal concentrations of dopamine, thereby providing effective control over activity of dopaminergic transmission. Since brain dopamine is known to be involved in numerous neuropsychiatric disorders, investigations using mice with genetically altered DAT function and thus intensity of dopamine-mediated signaling have provided numerous insights into the pathology of these disorders and novel pathological mechanisms that could be targeted to provide new therapeutic approaches for these disorders. In this brief overview, we discuss recent investigations involving animals with genetically altered DAT function, particularly focusing on translational studies providing new insights into pathology and pharmacology of dopamine-related disorders. Perspective applications of these and newly developed models of DAT dysfunction are also discussed.
Expert Review of Neurotherapeutics · 2014 · 56 citations · open access
VMAT2 and Parkinson’s disease: harnessing the dopamine vesicle
AbstractDespite a movement away from dopamine-focused Parkinson's disease (PD) research, a recent surge of evidence now suggests that altered vesicular storage of dopamine may contribute to the demise of the nigral neurons in this disease. Human studies demonstrate that the vesicular monoamine transporter 2 (VMAT2; SLC18A2) is dysfunctional in PD brain. Moreover, studies with transgenic mice suggest that there is an untapped reserve capacity of the dopamine vesicle that could be unbridled by increasing VMAT2 function. Therapeutic manipulation of VMAT2 level or function has the potential to improve efficacy of dopamine derived from administered levodopa, increase dopamine neurotransmission from remaining midbrain dopamine neurons and protect against neurotoxic insults. Thus, the development of drugs to enhance the storage of release of dopamine may be a fruitful avenue of research for PD.
Journal of Clinical Psychopharmacology · 2007 · 34 citations
Displacement of Serotonin and Dopamine Transporters by Venlafaxine Extended Release Capsule at Steady State
AbstractBoth positron emission tomography and single photon emission computed tomography (SPECT) studies suggest that saturation of serotonin transporters (SERT) is present during treatment with therapeutic doses of selective serotonin reuptake inhibitors (SSRIs). Selective serotonin reuptake inhibitors also appear to increase the availability of dopamine transporters (DAT). The current study measured SERT occupancy and modulation of DAT by the serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine using [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane SPECT. Eight healthy subjects were administered open-label venlafaxine extended release capsules (75 mg/d for 4 days followed by 150 mg/d for 5 days). Venlafaxine significantly inhibited [123I]beta-CIT binding to SERT in the brainstem (55.4%) and the diencephalon (54.1%). In contrast, venlafaxine increased [123I]beta-CIT binding to DAT in the striatum (10.1%) after 5 days of administration of 150 mg/d. The displacement of [123I]beta-CIT from brain SERT and the increase in striatal [123I]beta-CIT binding to DAT appear similar to previous work with the SSRI citalopram (40 mg/d). A literature review of SERT occupancy by marketed SSRIs and the SNRI venlafaxine using SPECT ([123I]beta-CIT) or positron emission tomography ([11C](N, N-Dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine) imaging suggests that therapeutic doses of SNRI are associated with virtual saturation of the serotonin transporter.
A novel missense variant in <i>SLC18A2</i> causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets
AbstractBACKGROUND: , 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.
Monoamine Transporters: Basic Biology with Clinical Implications
AbstractBiogenic amine transporters mediate two important steps in the reuptake and recycling of monoamines released by neurons in the central nervous system. First, high-affinity transporters found in the plasma membrane of neurons and glial cells mediate the removal of neurotransmitter from the extracellular space, thus terminating the action of the monoamines serotonin, norepinephrine, and dopamine. Within the cell, vesicular transporters repackage monoamines into vesicles for additional cycles of release. Two gene families are involved in the transport of the biogenic amines—the Na + /Cl - -dependent plasma membrane carriers and the H+-dependent vesicular amine carriers. These transporters are known to regulate neurotransmitter con centrations in monoaminergic pathways and are the primary targets for a wide variety of clinically important antidepressants, antihypertensives, stimulants, and stimulant drugs of abuse. The Neuroscientist 1:259-267, 1995
Zenodo (CERN European Organization for Nuclear Research) · 2025 · 0 citations · open access
TRANSVERSAL PATCH ON HUNTINGTONS DISEASES
AbstractHuntington's disease (HD) is a progressive neurodegenerative disorder marked by motor impairment, cognitive decline, and psychiatric symptoms. Deutetrabenazine, a deuterated analog of tetrabenazine, is an FDA-approved medication that alleviates chorea in HD patients by inhibiting vesicular monoamine transporter 2 (VMAT2), which modulates dopamine levels in the brain. However, oral administration of Deutetrabenazine can result in variable drug absorption, fluctuating plasma concentrations, and gastrointestinal side effects, posing challenges for consistent management of symptoms. This study investigates a novel transversal approach to enhance Deutetrabenazine delivery using a transdermal patch. The proposed transdermal delivery system aims to provide a continuous, controlled release of Deutetrabenazine, improving pharmacokinetics, reducing peak-trough fluctuations, and enhancing patient compliance. Furthermore, the transdermal patch may be designed to co-deliver complementary therapeutic agents targeting other disease aspects, such as neuroprotection or inflammation, to offer a multimodal treatment strategy. This research explores the feasibility, effectiveness, and patient acceptability of this transdermal system, with the potential to provide more consistent symptom control and address the underlying neurodegenerative processes of Huntington's disease.
Reserpine inhibits stylet thrusting triggered by endogenous, but not exogenous, serotonin.
Abstract<p><b>A.</b> The cartoon provides a rationale for the differential effect of reserpine on the response to serotonin and fluoxetine. It depicts a serotonergic synapse, with the pre-synapse as the site of serotonin synthesis and release and the post-synapse which harbours serotonin receptors. In mammalian systems reserpine acts presynaptically to deplete the storage of the neurotransmitter serotonin (shown as open red circles) by preventing its uptake into vesicles (shown as solid red circles) by inhibition of the vesicular monoamine transporter, VMAT, present on the vesicle membrane [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1008884#ppat.1008884.ref014" target="_blank">14</a>]. This prevents storage of serotonin and results in a lack of serotonin presynaptically and an inability of the presynaptic terminal to release serotonin. Fluoxetine (Prozac) on the other hand blocks the plasma membrane serotonin transporter, SERT. This prevents the reuptake of serotonin into the presynaptic terminal following its release. Thus, fluoxetine increases synaptic levels of serotonin (shown by open red circles) and in this way fluoxetine can act indirectly to stimulate transmission at the serotonergic synapse. This effect of fluoxetine is susceptible to block by reserpine as it requires endogenous serotonin to elicit its effect. However, the response to exogenous serotonin circumvents reserpine inhibition as it acts directly on the postsynaptic receptors. <b>B</b>. The <i>G</i>. <i>pallida</i> stylet is a lance-like structure that can be thrust out of the mouth of the nematode (in this image it is shown in the retracted position) in a rhythmic manner to initiate hatching and root invasion. Inside the root it is used for migration and to support feeding and interaction with the host. The activity of the stylet can be visually scored by counting the number of thrusts made in 1 min. Scale bar ~ 20 μm. <b>C.</b> J2s were incubated in either serotonin or fluoxetine at the concentrations indicated for 1 h and then the number of stylet thrusts made in 1 min was counted. Data are mean ± s.e.m.; n = 8 to 17 J2s for each time point. <b>D.</b> Reserpine blocked the stylet response to fluoxetine but not serotonin. J2s were pre-soaked in reserpine at the concentration indicated for 24 h and subsequently immersed in either 10 mM serotonin or 2 mM fluoxetine for 30 min and stylet thrusting scored for 1 min. Data are mean ± s.e.m.; n = 10 J2s for each data point.</p>
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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