-
Cells Jun 2023Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function... (Review)
Review
Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the gene. Advances in genomic analysis have revealed an evolving spectrum of -related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy.
Topics: Dopamine Plasma Membrane Transport Proteins; Precision Medicine; Phenotype
PubMed: 37443770
DOI: 10.3390/cells12131737 -
Biomolecules May 2023The key element of dopamine (DA) neurotransmission is undoubtedly DA transporter (DAT), a transmembrane protein responsible for the synaptic reuptake of the mediator.... (Review)
Review
The key element of dopamine (DA) neurotransmission is undoubtedly DA transporter (DAT), a transmembrane protein responsible for the synaptic reuptake of the mediator. Changes in DAT's function can be a key mechanism of pathological conditions associated with hyperdopaminergia. The first strain of gene-modified rodents with a lack of DAT were created more than 25 years ago. Such animals are characterized by increased levels of striatal DA, resulting in locomotor hyperactivity, increased levels of motor stereotypes, cognitive deficits, and other behavioral abnormalities. The administration of dopaminergic and pharmacological agents affecting other neurotransmitter systems can mitigate those abnormalities. The main purpose of this review is to systematize and analyze (1) known data on the consequences of changes in DAT expression in experimental animals, (2) results of pharmacological studies in these animals, and (3) to estimate the validity of animals lacking DAT as models for discovering new treatments of DA-related disorders.
Topics: Animals; Rodentia; Dopamine Plasma Membrane Transport Proteins; Corpus Striatum; Dopamine; Synaptic Transmission
PubMed: 37238676
DOI: 10.3390/biom13050806 -
International Journal of Molecular... Oct 2021A major goal of current clinical research in Parkinson's disease (PD) is the validation and standardization of biomarkers enabling early diagnosis, predicting outcomes,... (Review)
Review
A major goal of current clinical research in Parkinson's disease (PD) is the validation and standardization of biomarkers enabling early diagnosis, predicting outcomes, understanding PD pathophysiology, and demonstrating target engagement in clinical trials. Molecular imaging with specific dopamine-related tracers offers a practical indirect imaging biomarker of PD, serving as a powerful tool to assess the status of presynaptic nigrostriatal terminals. In this review we provide an update on the dopamine transporter (DAT) imaging in PD and translate recent findings to potentially valuable clinical practice applications. The role of DAT imaging as diagnostic, preclinical and predictive biomarker is discussed, especially in view of recent evidence questioning the incontrovertible correlation between striatal DAT binding and nigral cell or axon counts.
Topics: Animals; Biomarkers; Dopamine Plasma Membrane Transport Proteins; Humans; Molecular Imaging; Parkinson Disease
PubMed: 34681899
DOI: 10.3390/ijms222011234 -
Rhode Island Medical Journal (2013) Sep 2023The Dopamine Transporter Scan (DaT) is a radionuclear imaging technique which was approved by the FDA to differentiate essential tremor (ET) from Parkinson's disease... (Review)
Review
The Dopamine Transporter Scan (DaT) is a radionuclear imaging technique which was approved by the FDA to differentiate essential tremor (ET) from Parkinson's disease (PD). The scan is a crude indicator of the number of dopamine-secreting cells and is abnormal in presynaptic parkinsonian syndromes. In this article we review this and other possible clinical situations in which a DaT scan may be useful.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Parkinsonian Disorders; Parkinson Disease; Radionuclide Imaging
PubMed: 37643339
DOI: No ID Found -
American Journal of Medical Genetics.... Mar 2018The dopamine transporter (DAT) is one of the most relevant and investigated neurotransmitter transporters. DAT is a plasma membrane protein which plays a homeostatic... (Review)
Review
The dopamine transporter (DAT) is one of the most relevant and investigated neurotransmitter transporters. DAT is a plasma membrane protein which plays a homeostatic role, controlling both extracellular and intracellular concentrations of dopamine (DA). Since unbalanced DA levels are known to be involved in numerous mental disorders, a wealth of investigations has provided valuable insights concerning DAT role into normal brain functioning and pathological processes. Briefly, this extensive but non-systematic review discusses what is recently known about the role of SLC6A3 gene which encodes the dopamine transporter in psychiatric phenotypes. DAT protein, SLC6A3 gene, animal models, neuropsychology, and neuroimaging investigations are also concisely discussed. To conclude, current challenges are reviewed in order to provide perspectives for future studies.
Topics: Animals; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Mental Disorders; Phenotype
PubMed: 28766921
DOI: 10.1002/ajmg.b.32578 -
Journal of Neurogenetics Mar 2016The dopamine transporter (DAT) plays an important homeostatic role in the control of both the extracellular and intraneuronal concentrations of dopamine, thereby... (Review)
Review
The 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.
Topics: Animals; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Mice; Translational Research, Biomedical
PubMed: 27276191
DOI: 10.3109/01677063.2016.1144751 -
Journal of Chemical Neuroanatomy Oct 2017The dopamine transporter (DAT) is a plasma membrane phosphoprotein that actively translocates extracellular dopamine (DA) into presynaptic neurons. The transporter is... (Review)
Review
The dopamine transporter (DAT) is a plasma membrane phosphoprotein that actively translocates extracellular dopamine (DA) into presynaptic neurons. The transporter is the primary mechanism for control of DA levels and subsequent neurotransmission, and is the target for abused and therapeutic drugs that exert their effects by suppressing reuptake. The transport capacity of DAT is acutely regulated by signaling systems and drug exposure, providing neurons the ability to fine-tune DA clearance in response to specific conditions. Kinase pathways play major roles in these mechanisms, and this review summarizes the current status of DAT phosphorylation characteristics and the evidence linking transporter phosphorylation to control of reuptake and other functions. Greater understanding of these processes may aid in elucidation of their possible contributions to DA disease states and suggest specific phosphorylation sites as targets for therapeutic manipulation of reuptake.
Topics: Animals; Dopamine Plasma Membrane Transport Proteins; Humans; Phosphorylation; Protein Processing, Post-Translational
PubMed: 27836487
DOI: 10.1016/j.jchemneu.2016.10.004 -
Brain, Behavior, and Immunity May 2018The second-most common neurodegenerative disease, Parkinson's Disease (PD) has three hallmarks: dysfunctional dopamine transmission due, at least in part, to dopamine... (Review)
Review
The second-most common neurodegenerative disease, Parkinson's Disease (PD) has three hallmarks: dysfunctional dopamine transmission due, at least in part, to dopamine neuron degeneration; intracellular inclusions of α-synuclein aggregates; and neuroinflammation. The origin and interplay of these features remains a puzzle, as does the underlying mechanism of PD pathogenesis and progression. When viewed in the context of neuroimmunology, dopamine also plays a role in regulating peripheral immune cells. Intriguingly, plasma dopamine levels are altered in PD, suggesting collateral dysregulation of peripheral dopamine transmission. The dopamine transporter (DAT), the main regulator of dopaminergic tone in the CNS, is known to exist in lymphocytes and monocytes/macrophages, but little is known about peripheral DAT biology or how DAT regulates the dopaminergic tone, much less how peripheral DAT alters immune function. Our review is guided by the hypothesis that dysfunctional peripheral dopamine signaling might be linked to the dysfunctional immune responses in PD and thereby suggests a potential bidirectional communication between central and peripheral dopamine systems. This review seeks to foster new perspectives concerning PD pathogenesis and progression.
Topics: Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Humans; Lymphocytes; Macrophages; Monocytes; Nerve Degeneration; Neurodegenerative Diseases; Parkinson Disease; Signal Transduction; alpha-Synuclein
PubMed: 29551693
DOI: 10.1016/j.bbi.2018.03.020 -
Journal of Chemical Neuroanatomy Oct 2017The neurotransmitter dopamine (DA) plays a key role in several biological processes including reward, mood, motor activity and attention. Synaptic DA homeostasis is... (Review)
Review
The neurotransmitter dopamine (DA) plays a key role in several biological processes including reward, mood, motor activity and attention. Synaptic DA homeostasis is controlled by the dopamine transporter (DAT) which transports extracellular DA into the presynaptic neuron after release and regulates its availability to receptors. Many neurological disorders such as schizophrenia, bipolar disorder, Parkinson disease and attention-deficit hyperactivity disorder are associated with imbalances in DA homeostasis that may be related to DAT dysfunction. DAT is also a target of psychostimulant and therapeutic drugs that inhibit DA reuptake and lead to elevated dopaminergic neurotransmission. We have recently demonstrated the acute and chronic modulation of DA reuptake activity and DAT stability through S-palmitoylation, the linkage of a 16-carbon palmitate group to cysteine via a thioester bond. This review summarizes the properties and regulation of DAT palmitoylation and describes how it serves to affect various transporter functions. Better understanding of the role of palmitoylation in regulation of DAT function may lead to identification of therapeutic targets for modulation of DA homeostasis in the treatment of dopaminergic disorders.
Topics: Animals; Dopamine Plasma Membrane Transport Proteins; Humans; Lipoylation; Protein Processing, Post-Translational
PubMed: 28115272
DOI: 10.1016/j.jchemneu.2017.01.002 -
Molecular Psychiatry Feb 2022The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk...
The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region's functional markers such as DNPi (rs67175440) and 5'VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.
Topics: Attention Deficit Disorder with Hyperactivity; Dopamine Plasma Membrane Transport Proteins; Haplotypes; Humans; Mutation; Phenotype
PubMed: 34650206
DOI: 10.1038/s41380-021-01341-5