Zn2+ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder

Hamilton, Peter J.; Shekar, Aparna; Belovich, Andrea N.; Christianson, Nicole Bibus; Campbell, Nicholas G.; Sutcliffe, James S.; Galli, Aurelio; Matthies, Heinrich J.G.; Erreger, Kevin

doi:10.1186/s13229-015-0002-7

Cited by 19 publications

(17 citation statements)

References 12 publications

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“…Our assessment of structural changes in T356M showed, in agreement with recent findings (53), that Zn 2+ partly rescues uptake function of T356M. A similar Zn…”

Section: Discussionsupporting

confidence: 92%

“…Remarkably, Zn 2+ produced even larger MTSET-dependent inhibition of dopamine uptake for both T356M (~80%), and D421N (~75%) even though these variants display opposite conformational preferences in the absence of Zn 2+ . The molecular mechanisms underlying Zn 2+ -dependent rescue of T356M function are highly interesting, and could provide important insight into molecular mechanisms of allosteric activators of DAT, which has been suggested to hold therapeutic potential (47,53 . Trace recordings of voltage clamped oocytes showed that dopamine indeed elicits an aberrant outward current through T356M (Fig.…”

Section: +mentioning

confidence: 99%

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Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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Genetic factors are known to significantly contribute to the etiology of psychiatric diseases such as attention deficit hyperactivity disorder (ADHD) and autism spectrum and bipolar disorders, but the underlying molecular processes remain largely elusive. The dopamine transporter (DAT) has received continuous attention as a potential risk factor for psychiatric disease, as it is critical for dopamine homeostasis and serves as principal target for ADHD medications. Constrain metrics for the DAT-encoding gene solute carrier family 6 member 3 (SLC6A3) indicate that missense mutations are under strong negative selection, pointing to pathophysiological outcomes when DAT function is compromised. Here, we systematically characterized six rare genetic variants of DAT (I312F, T356M, D421N, A559V, E602G, and R615C) identified in patients with neuropsychiatric disorders. We evaluated dopamine uptake and ligand interactions, along with ion coordination and electrophysiological properties, to elucidate functional phenotypes, and applied Zn 2+ exposure and a substituted cysteineaccessibility approach to identify shared structural changes. Three variants (I312F, T356M, and D421N) exhibited impaired dopamine uptake associated with changes in ligand binding, ion coordination, and distinct conformational disturbances. Remarkably, we found that all three variants displayed gain-offunction electrophysiological phenotypes. I312F mediated an increased uncoupled anion conductance previously suggested to modulate neuronal excitability. T356M and D421N both mediated a cocaine-sensitive leakage of cations, which for T356M, was potentiated by Zn 2+ , concurrent with partial functional rescue. Collectively, our findings support that gain of disruptive functions due to missense mutations in SLC6A3 may be key to understanding how dopaminergic dyshomeostasis arises in heterozygous carriers.A substantial proportion of the disease etiology of common psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder, and schizophrenia is attributed genetic components (1). The underlying neurobiological mechanisms are not clear, but dopamine disturbances are believed to constitute a central component (2-7). The allelic spectrum of these dopamine-related disorders is rapidly expanding and comprises both common variants and rare structural or exonic mutations, including de novo variants (1,(8)(9)(10)(11)(12). Moreover, an interesting overlap in the genetic architecture of psychiatric disorders has been observed, and this pleiotrophy is seen for both common and rare variants (13)(14)(15)(16)(17)(18). Despite progress, much of the genetic component remains unaccounted for, and we also have the challenge ahead of translating most of the comprehensive genetic information into an understanding of underlying biological processes, and subsequently into clinically applicable knowledge. Rare variants may provide a unique handle for obtaining new disease insights as they are expected to h...

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“…Our assessment of structural changes in T356M showed, in agreement with recent findings (53), that Zn 2+ partly rescues uptake function of T356M. A similar Zn…”

Section: Discussionsupporting

confidence: 92%

Section: +mentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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“…Maternal inflammation has been previously shown to cause offspring deficits in latent and prepulse inhibition, along with decreased social and exploratory behavior (Smith et al, 2007), which are associated with dopamine dysfunction and mental health disorders such as schizophrenia and ASD. The increased inflammation that accompanies maternal HFD consumption likely impacts the dopaminergic system of offspring, causing increased risk of psychopathology as changes in the dopaminergic system are associated with disorders such as ASD(Bowton et al, 2014; Hamilton et al, 2015; Staal, 2014), ADHD (Hasler et al, 2015; Pan et al, 2015; Tong et al, 2015), schizophrenia (Howes et al, 2015; Slifstein et al, 2015; Sumiyoshi et al, 2014), anxiety (Agius et al, 2014; Lee et al, 2015), and depression (Clausius et al, 2009; Dunlop and Nemeroff, 2007). …”

Section: Mechanisms By Which Maternal High-fat Diet Consumption mentioning

confidence: 99%

Maternal high-fat diet programming of the neuroendocrine system and behavior

Sullivan

Riper

Lockard

et al. 2015

Hormones and Behavior

145

108

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Maternal obesity, metabolic state, and diet during gestation have profound effects on offspring development. The prevalence of neurodevelopmental and mental health disorders has risen rapidly in the last several decades in parallel with the rise in obesity rates. Evidence from epidemiological studies indicates that maternal obesity and metabolic complications increase the risk of offspring developing behavioral disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and schizophrenia. Animal models show that a maternal diet high in fat similarly disrupts behavioral programming of offspring, with animals showing social impairments, increased anxiety and depressive behaviors, reduced cognitive development, and hyperactivity. Maternal obesity, metabolic conditions, and high fat diet consumption increase maternal leptin, insulin, glucose, triglycerides, and inflammatory cytokines. This leads to increased risk of placental dysfunction, and altered fetal neuroendocrine development. Changes in brain development that likely contribute to the increased risk of behavioral and mental health disorders include increased inflammation in the brain, as well as alterations in the serotonergic system, dopaminergic system and hypothalamic pituitary adrenal (HPA) axis.

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“…DAT has been implicated in ADHD by the efficacy of stimulant medications, which treat the disorder and block the DAT (Yanli Zhang-James, 2015) along with suggestive findings from genetic association studies (Faraone et al, 1999; Faraone et al, 2014). Some reports of DAT associated with ASD and ADHD have focused on mutations, such as the V559 and the T356M variants, that cause the transporter to anomalously efflux dopamine into the synaptic cleft (Hamilton et al, 2015; Mazei-Robison et al, 2008). In addition to anomalous dopamine efflux during basal level neurotransmission, the V559 coding variant was found in two autism probands and was found to have trafficking disruptions (Bowton et al, 2014).…”

Section: : Reviewmentioning

confidence: 99%

Endosomal system genetics and autism spectrum disorders: A literature review

Patak

Zhang-James

Faraone

2016

Neuroscience & Biobehavioral Reviews

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Autism spectrum disorders (ASDs) are a group of debilitating neurodevelopmental disorders thought to have genetic etiology, due to their high heritability. The endosomal system has become increasingly implicated in ASD pathophysiology. In an attempt to summarize the association between endosomal system genes and ASDs we performed a systematic review of the literature. We searched PubMed for relevant articles. Simons Foundation Autism Research Initiative (SFARI) gene database was used to exclude articles regarding genes with less than minimal evidence for association with ASDs. Our search retained 55 articles reviewed in two categories: genes that regulate and genes that are regulated by the endosomal system. Our review shows that the endosomal system is a novel pathway implicated in ASDs as well as other neuropsychiatric disorders. It plays a central role in aspects of cellular physiology on which neurons and glial cells are particularly reliant, due to their unique metabolic and functional demands. The system shows potential for biomarkers and pharmacological intervention and thus more research into this pathway is warranted.

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Zn2+ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder

Cited by 19 publications

References 12 publications

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Maternal high-fat diet programming of the neuroendocrine system and behavior

Endosomal system genetics and autism spectrum disorders: A literature review

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