{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC1A4, which encodes the ASCT1 protein, is a Na⁺‐dependent neutral amino acid transporter that plays an essential role in brain physiology by mediating the uptake of key amino acids—including L‐serine, alanine, threonine, cysteine, and even glutamate—into neurons. Within the brain, L‐serine is primarily synthesized in astrocytes and is pivotal for neuronal differentiation and function; ASCT1 thereby serves as the conduit for transferring L‐serine and related substrates to neurons, a process critical for synaptic transmission and plasticity. Furthermore, evidence indicates that ASCT1 influences extracellular d‐serine levels, which in turn modulate NMDA receptor activity and long‐term potentiation, underlining its importance in normal neurophysiology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in amino acid transport, SLC1A4 has emerged as a viral receptor that is exploited by retroviral particles. Studies have demonstrated that the envelope glycoprotein of human endogenous retrovirus type W (HERV‐W) utilizes both ASCT2 (SLC1A5) and its paralog ASCT1 (SLC1A4) to mediate cell–cell fusion and pseudotyped viral infection, a dual receptor use that may have provided an evolutionary advantage to these retroviruses. Moreover, the trafficking and recycling of ASCT1 from the cell surface have been shown to require the coordinated action of the retromer and the actin‐polymerizing WASH complex."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in SLC1A4 disrupt amino acid transport and have been causally linked to a spectrum of severe neurodevelopmental disorders. Patients carrying pathogenic variants present with global developmental delay, progressive microcephaly, seizures, spasticity, and thinning of the corpus callosum, underscoring the critical role of ASCT1 in maintaining neuronal amino acid homeostasis. Exome analyses and case studies have identified deleterious missense and truncating mutations in SLC1A4, and although rare, some variants may exhibit population‐specific distributions. In parallel, genetic association studies have also suggested links between SLC1A4 polymorphisms and disorders such as multiple system atrophy, while assessments in schizophrenia and bipolar disorder have yielded inconclusive findings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical and structural investigations have further elucidated the mechanistic underpinnings of SLC1A4 function. ASCT1 has been shown to support a concentrative, sodium‐dependent transport of substrates with distinct kinetic properties—features that are modulated by specific amino acid residues and post‐translational modifications such as N‐linked glycosylation. These structural determinants not only influence substrate affinity and transport rates but may also affect the efficiency of viral docking and receptor recycling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nadirah Damseh, Alexandre Simonin, Chaim Jalas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmedgenet-2015-103104"}], "href": "https://doi.org/10.1136/jmedgenet-2015-103104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26041762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26041762"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "J Pinilla, A Barber, M P Lostao "}, {"type": "b", "children": [{"type": "t", "text": "Active transport of alanine by the neutral amino-acid exchanger ASCT1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Can J Physiol Pharmacol (2001)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11824937"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11824937"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Alan C Foster, Natalie Rangel-Diaz, Ursula Staubli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuropharmacology (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuropharm.2017.08.010"}], "href": "https://doi.org/10.1016/j.neuropharm.2017.08.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28807674"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28807674"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Dimitri Lavillette, Mariana Marin, Alessia Ruggieri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters/cell surface receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/jvi.76.13.6442-6452.2002"}], "href": "https://doi.org/10.1128/jvi.76.13.6442-6452.2002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12050356"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12050356"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mariana Marin, Dimitri Lavillette, Sean M Kelly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "N-linked glycosylation and sequence changes in a critical negative control region of the ASCT1 and ASCT2 neutral amino acid transporters determine their retroviral receptor functions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/jvi.77.5.2936-2945.2003"}], "href": "https://doi.org/10.1128/jvi.77.5.2936-2945.2003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12584318"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12584318"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Arunas Kvainickas, Ana Jimenez Orgaz, Heike Nägele, et al. 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