Slc1a4, also known as alanine-serine-cysteine transporter 1 (ASCT1), is a gene encoding a Na-dependent neutral amino acid transporter. It helps maintain amino acid balance in the brain and periphery, playing a crucial role in transporting L-and D-isomers of serine. L-serine is essential for protein and sphingolipid synthesis, while D-serine is a co-agonist for normal neurotransmission through N-methyl-D-aspartate receptors. Slc1a4 is involved in pathways related to cell cycle, metabolism, and cancer-related processes [1,2].

In Slc1a4 knockout mouse models, acute inhibition or deletion of Slc1a4 leads to decreased serine influx into the brain, resulting in microcephaly, decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioural impairments. Oral administration of L-serine can rescue these biochemical and behavioural changes [3]. In ASCT1-KO mice, lower levels of brain D-serine and higher levels of L-alanine, L-threonine, and glycine were observed, along with neurodevelopmental alterations and deficits in motor function, spatial learning, and affective behavior [5].

In conclusion, Slc1a4 is essential for maintaining serine homeostasis in the brain, which is crucial for normal neurodevelopment and brain function. The study of Slc1a4 KO mouse models has provided valuable insights into the role of Slc1a4 in neurodevelopmental and neurodegenerative disorders, as well as in metabolic microcephaly. Additionally, Slc1a4 may have implications in cancer, such as hepatocellular carcinoma, where it is related to cell proliferation, migration, and apoptosis [2,4].

References:

1. Elazar, Dana, Alvarez, Natalie, Drobeck, Sabrina, Gunn, Teresa M. 2025. SLC1A4 and Serine Homeostasis: Implications for Neurodevelopmental and Neurodegenerative Disorders. In International journal of molecular sciences, 26, . doi:10.3390/ijms26052104. https://pubmed.ncbi.nlm.nih.gov/40076728/

2. Peng, Xiaozhen, Chen, Ruochan, Cai, Shenglan, Lu, Shanshan, Zhang, Yiya. 2021. SLC1A4: A Powerful Prognostic Marker and Promising Therapeutic Target for HCC. In Frontiers in oncology, 11, 650355. doi:10.3389/fonc.2021.650355. https://pubmed.ncbi.nlm.nih.gov/33777811/

3. Odeh, Maali, Sajrawi, Clara, Majcher, Adam, Radzishevsky, Inna, Wolosker, Herman. . A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations. In Brain : a journal of neurology, 147, 3874-3889. doi:10.1093/brain/awae134. https://pubmed.ncbi.nlm.nih.gov/38662784/

4. Zheng, Jiaoyun, Gong, Jian. 2025. SLC1A4 Promotes Malignant Transformation of Hepatocellular Carcinoma by Activating the AKT Signaling. In Analytical cellular pathology (Amsterdam), 2025, 1115184. doi:10.1155/ancp/1115184. https://pubmed.ncbi.nlm.nih.gov/39949345/

5. Kaplan, Eitan, Zubedat, Salman, Radzishevsky, Inna, Avital, Avi, Wolosker, Herman. 2018. ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d-serine and neurodevelopment. In Proceedings of the National Academy of Sciences of the United States of America, 115, 9628-9633. doi:10.1073/pnas.1722677115. https://pubmed.ncbi.nlm.nih.gov/30185558/