Choroid plexus LAT2 and SNAT3 as partners in CSF amino acid homeostasis maintenance

Dolgodilina, Elena; Camargo, Simone M. R.; Roth, E.; Herzog, Brigitte; Nunes, Virginia; Palacı́n, Manuel; Verrey, François

doi:10.1186/s12987-020-0178-x

Cited by 16 publications

(7 citation statements)

References 41 publications

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“…Alternatively, since available biochemical assays assess non-cellular fluids, it is possible that the astrocytes are retaining glutamine and the redundancy of SNAT5 and the possible upregulation of choroid plexus LAT2 could have moderated the glutamine phenotype. 12,45 Additionally, similar to the null mice, severe gait impairment and hypotonia were prominent neurological features we observed in association with human SLC38A3 potential LoF alleles.…”

Section: Snat5 Has a Similar Expression Pattern And Performs Many Of ...supporting

confidence: 74%

Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

Marafi

Fatih

Kaiyrzhanov

et al. 2021

Brain

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The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy (DEE) and severe neurodevelopmental disorders (NDDs). Exome sequencing and family-based rare variant analyses on a cohort with NDD identified two siblings with DEE and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar DEE phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and cerebrospinal fluid of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for DEE and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

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Section: Snat5 Has a Similar Expression Pattern And Performs Many Of ...supporting

confidence: 74%

Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

Marafi

Fatih

Kaiyrzhanov

et al. 2021

Brain

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“…MCT8 and SNAT3 are both highly expressed in choroid plexus epithelial cells, but also detected in other brain cell types, albeit the latter predominantly in barrier-related cells, such as vascular endothelial cells, pericytes and ependymal cells [ 71 ]. MCT8 is involved in thyroxine transport [ 73 ] while SNAT3 contributes to the high glutamine content of the CSF [ 74 ]. None of these has, as of yet, been investigated for a potential implication in CSF secretion.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of transport mechanisms and regulatory pathways in rat choroid plexus

Andreassen

Toft-Bertelsen

Wardman

et al. 2022

Fluids Barriers CNS

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Background Dysregulation of brain fluid homeostasis associates with brain pathologies in which fluid accumulation leads to elevated intracranial pressure. Surgical intervention remains standard care, since specific and efficient pharmacological treatment options are limited for pathologies with disturbed brain fluid homeostasis. Such lack of therapeutic targets originates, in part, from the incomplete map of the molecular mechanisms underlying cerebrospinal fluid (CSF) secretion by the choroid plexus. Methods The transcriptomic profile of rat choroid plexus was generated by RNA Sequencing (RNAseq) of whole tissue and epithelial cells captured by fluorescence-activated cell sorting (FACS), and compared to proximal tubules. The bioinformatic analysis comprised mapping to reference genome followed by filtering for type, location, and association with alias and protein function. The transporters and associated regulatory modules were arranged in discovery tables according to their transcriptional abundance and tied together in association network analysis. Results The transcriptomic profile of choroid plexus displays high similarity between sex and species (human, rat, and mouse) and lesser similarity to another high-capacity fluid-transporting epithelium, the proximal tubules. The discovery tables provide lists of transport mechanisms that could participate in CSF secretion and suggest regulatory candidates. Conclusions With quantification of the transport protein transcript abundance in choroid plexus and their potentially linked regulatory modules, we envision a molecular tool to devise rational hypotheses regarding future delineation of choroidal transport proteins involved in CSF secretion and their regulation. Our vision is to obtain future pharmaceutical targets towards modulation of CSF production in pathologies involving disturbed brain water dynamics.

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“…MCT8 and SNAT3 are both highly expressed in choroid plexus epithelial cells, but also detected in other brain cell types, albeit the latter predominantly in barrier- related cells, such as vascular endothelial cells, pericytes and ependymal cells [68]. MCT8 is involved in thyroxine transport [70] while SNAT3 contributes to the high glutamine content of the CSF [71]. None of these has, as of yet, been investigated for a potential implication in CSF secretion.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of transport mechanisms and regulatory pathways in rat choroid plexus

Andreassen¹,

Toft-Bertelsen²,

Wardman³

et al. 2022

Preprint

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Background: Dysregulation of brain fluid homeostasis associates with brain pathologies in which fluid accumulation leads to elevated intracranial pressure. Surgical intervention remains standard care, since specific and efficient pharmacological treatment options are limited for pathologies with disturbed brain fluid homeostasis. Such lack of therapeutic targets originates, in part, from the incomplete map of the molecular mechanisms underlying cerebrospinal fluid (CSF) secretion by the choroid plexus. Methods: The transcriptomic profile of rat choroid plexus was generated by RNA Sequencing (RNAseq) of whole tissue and epithelial cells captured by fluorescence-activated cell sorting (FACS), and compared to proximal tubules. The bioinformatic analysis comprised mapping to reference genome followed by filtering for type, location, and association with alias and protein function. The transporters and associated regulatory modules were arranged in discovery tables according to their transcriptional abundance and tied together in association network analysis. Results: The transcriptomic profile of choroid plexus displays high similarity between sex and species (human, rat, and mouse) and lesser similarity to another secretory epithelium, the proximal tubules. The discovery tables provide lists of transport mechanisms that could participate in CSF secretion and suggest regulatory candidates. Conclusions: With quantification of the transport protein abundance in choroid plexus and their potentially linked regulatory modules, we envision a molecular tool to devise rational hypotheses regarding future delineation of choroidal transport proteins involved in CSF secretion and their regulation. Our vision is to obtain pharmaceutical targets towards modulation of CSF production in pathologies involving disturbed brain water dynamics.

show abstract

Choroid plexus LAT2 and SNAT3 as partners in CSF amino acid homeostasis maintenance

Cited by 16 publications

References 41 publications

Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

Transcriptional profiling of transport mechanisms and regulatory pathways in rat choroid plexus

Transcriptional profiling of transport mechanisms and regulatory pathways in rat choroid plexus

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