Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder

Tarlungeanu, Dora-Clara; Deliu, Elena; Dotter, Christoph P.; Kara, Majdi; Janiesch, Philipp Christoph; Scalise, Mariafrancesca; Galluccio, Michele; Tesulov, Mateja; Morelli, Emanuela; Sönmez, Fatma Müjgan; Bilgüvar, Kaya; Ohgaki, Ryuichi; Kanai, Yoshikatsu; Johansen, Anide; Esharif, Seham; Ben‐Omran, Tawfeg; Topçu, Meral; Schlessinger, Avner; Indiveri, Cesare; Duncan, Kent E.; Çağlayan, Ahmet Okay; Günel, Murat; Gleeson, Joseph G.; Novarino, Gaia

doi:10.1016/j.cell.2016.11.013

Cited by 287 publications

(262 citation statements)

References 53 publications

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“…Impaired amino acid transport across the blood-brain barrier has been previously associated with ASD in mice and humans, 15 have been previously reported in cultured human trophoblasts. Impaired amino acid transport across the blood-brain barrier has been previously associated with ASD in mice and humans, 15 have been previously reported in cultured human trophoblasts.…”

Section: Discussionmentioning

confidence: 68%

“…7 The expression of SLC transporters in both the placenta and the developing fetal brain is therefore crucial for mediating the transport of amino acids from maternal circulation to the developing fetus. 15,16 Nevertheless, this has not been fully examined in the context of MIA during neurodevelopment. [9][10][11] Furthermore, these changes can result in altered substrate disposition in maternal and fetal tissues.…”

Section: Introductionmentioning

confidence: 99%

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Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

McColl

Piquette‐Miller

2019

American J Rep Immunol

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Problem Maternal immune activation (MIA) during pregnancy is associated with increased chances of neurodevelopmental disorders including schizophrenia and autism spectrum disorder (ASD). However, the exact mechanism through which MIA contributes to altered neurodevelopment is unknown. Due to the important role that amino acids play in neurodevelopment, altered amino acid transport could play a role in neurodevelopmental disorders. Indeed, altered plasma concentrations of multiple amino acids have been reported in individuals with ASD or schizophrenia. Therefore, our objective was to determine whether virally mediated MIA induces changes in amino acid transporters in the placenta and fetal brain. Method of study Pregnant rats were administered poly(I:C) on gestational day 14, and placental and fetal tissues were collected 6, 24, and 48 hours later. Amino acid transporter expression was measured in the placenta and fetal brain using qPCR, Western blotting, and Simple Western. Free amino acid concentrations in the fetal brain were quantified using HPLC. Results Poly(I:C) increased mRNA expression of several amino acid transporters in the placenta and fetal brain over these timepoints. Conversely, poly(I:C) imposed significant decreases in the protein expression of ASCT1 and EAAT2 in placenta and expression of SNAT5, EAAT1, and GLYT1 in fetal brain. Functional consequences of altered transporter expression were demonstrated through widespread changes in the concentrations of free amino acids in the fetal brains. Conclusion Together, these results represent novel findings with the poly(I:C) MIA model and contribute to the understanding of how MIA during pregnancy potentially leads to neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

McColl

Piquette‐Miller

2019

American J Rep Immunol

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“…This group encompasses all carrier defects of essential molecules that must be transported through cellular membranes, inborn errors of non essential AA and FA synthesis and several pyrimidine disorders that affects the synthesis of cytidine, uridine and thymidine nucleosides and are treatable, like CAD deficiency, or the congenital orotic aciduria. The most paradigmatic IMD linked to brain carrier defects are SLC7A5 mutations, resulting in the defective transport of branched chain AA (BCAA), and MFSD2A deficiency resulting in the defective transport of essential FA such as docosahexanoic acid (DHA) . Interestingly, branched chain dehydrogenase kinase deficiency, which overactivates BCAA oxidation and leads to very low levels of BCAA as in SLC7A5 mutations, presents with a similarly severe neurodevelopmental disease .…”

Section: Classificationmentioning

confidence: 99%

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

Saudubray

Mochel

Lamari

et al. 2019

J of Inher Metab Disea

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In view of the rapidly expanding number of IMD discovered by next generation sequencing, we propose a simplified classification of IMD that mixes elements from a clinical diagnostic perspective and a pathophysiological approach based on three large categories. We highlight the increasing importance of complex molecule metabolism and its connection with cell biology processes. Small molecule disorders have biomarkers and are divided in two subcategories: accumulation and deficiency. Accumulation of small molecules leads to acute or progressive postnatal “intoxication”, present after a symptom‐free interval, aggravated by catabolism and food intake. These treatable disorders must not be missed! Deficiency of small molecules is due to impaired synthesis of compounds distal to a block or altered transport of essential molecules. This subgroup shares many clinical characteristics with complex molecule disorders. Complex molecules (like glycogen, sphingolipids, phospholipids, glycosaminoglycans, glycolipids) are poorly diffusible. Accumulation of complex molecules leads to postnatal progressive storage like in glycogen and lysosomal storage disorders. Many are treatable. Deficiency of complex molecules is related to the synthesis and recycling of these molecules, which take place in organelles. They may interfere with fœtal development. Most present as neurodevelopmental or neurodegenerative disorders unrelated to food intake. Peroxisomal disorders, CDG defects of intracellular trafficking and processing, recycling of synaptic vesicles, and tRNA synthetases also belong to this category. Only few have biomarkers and are treatable. Disorders involving primarily energy metabolism encompass defects of membrane carriers of energetic molecules as well as cytoplasmic and mitochondrial metabolic defects. This oversimplified classification is connected to the most recent available nosology of IMD.

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“…Slc7a5 and Slc7a8 are Na + -independent amino acid antiporters, typically taking up essential LNAA in exchange for glutamine [9] or histidine [10]. These include the essential amino acids leucine, isoleucine, phenylalanine, tryptophan, valine and methionine.…”

Section: Introductionmentioning

confidence: 99%

“…Both Slc7a5 and Slc7a8 genes encode members of the heteromeric amino acid transporter family of proteins which require a regulatory glycoprotein subunit (in this case 4F2hc/CD98/Slc3a2) to function correctly [13,14]. It also plays an important role in maintenance of critical amino acids in the brain [10]. Accordingly, Slc7a5 is over-expressed in many cancers [18,19] and induction of Slc7a5 is associated with periods of rapid cell growth and expansion during sustained activation of T lymphocytes [20].…”

Section: Introductionmentioning

confidence: 99%

Wnt regulates amino acid transporter Slc7a5 and so constrains the integrated stress response in mouse embryos

et al. 2019

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Amino acids are essential for cellular metabolism, and it is important to understand how nutrient supply is coordinated with changing energy requirements during embryogenesis. Here, we show that the amino acid transporter Slc7a5/Lat1 is highly expressed in tissues undergoing morphogenesis and that Slc7a5-null mouse embryos have profound neural and limb bud outgrowth defects. Slc7a5-null neural tissue exhibited aberrant mTORC1 activity and cell proliferation; transcriptomics, protein phosphorylation and apoptosis analyses further indicated induction of the integrated stress response as a potential cause of observed defects. The pattern of stress response gene expression induced in Slc7a5-null embryos was also detected at low level in wild-type embryos and identified stress vulnerability specifically in tissues undergoing morphogenesis. The Slc7a5-null phenotype is reminiscent of Wnt pathway mutants, and we show that Wnt/b-catenin loss inhibits Slc7a5 expression and induces this stress response. Wnt signalling therefore normally supports the metabolic demands of morphogenesis and constrains cellular stress. Moreover, operation in the embryo of the integrated stress response, which is triggered by pathogen-mediated as well as metabolic stress, may provide a mechanistic explanation for a range of developmental defects.

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Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder

Cited by 287 publications

References 53 publications

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

Wnt regulates amino acid transporter Slc7a5 and so constrains the integrated stress response in mouse embryos

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