Publications by authors named "Federico Miguez-Cabello"

4 Publications

  • Page 1 of 1

Disease-associated GRIN protein truncating variants trigger NMDA receptor loss-of-function.

Hum Mol Genet 2021 Feb;29(24):3859-3871

Neuroscience Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.

De novo GRIN variants, encoding for the ionotropic glutamate NMDA receptor subunits, have been recently associated with GRIN-related disorders, a group of rare paediatric encephalopathies. Current investigational and clinical efforts are focused to functionally stratify GRIN variants, towards precision therapies of this primary disturbance of glutamatergic transmission that affects neuronal function and brain. In the present study, we aimed to comprehensively delineate the functional outcomes and clinical phenotypes of GRIN protein truncating variants (PTVs)-accounting for ~20% of disease-associated GRIN variants-hypothetically provoking NMDAR hypofunctionality. To tackle this question, we created a comprehensive GRIN PTVs variants database compiling a cohort of nine individuals harbouring GRIN PTVs, together with previously identified variants, to build-up an extensive GRIN PTVs repertoire composed of 293 unique variants. Genotype-phenotype correlation studies were conducted, followed by cell-based assays of selected paradigmatic GRIN PTVs and their functional annotation. Genetic and clinical phenotypes meta-analysis revealed that heterozygous GRIN1, GRIN2C, GRIN2D, GRIN3A and GRIN3B PTVs are non-pathogenic. In contrast, heterozygous GRIN2A and GRIN2B PTVs are associated with specific neurological clinical phenotypes in a subunit- and domain-dependent manner. Mechanistically, cell-based assays showed that paradigmatic pathogenic GRIN2A and GRIN2B PTVs result on a decrease of NMDAR surface expression and NMDAR-mediated currents, ultimately leading to NMDAR functional haploinsufficiency. Overall, these findings contribute to delineate GRIN PTVs genotype-phenotype association and GRIN variants stratification. Functional studies showed that GRIN2A and GRIN2B pathogenic PTVs trigger NMDAR hypofunctionality, and thus accelerate therapeutic decisions for this neurodevelopmental condition.
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http://dx.doi.org/10.1093/hmg/ddaa220DOI Listing
February 2021

AMPAR/TARP stoichiometry differentially modulates channel properties.

Elife 2020 05 26;9. Epub 2020 May 26.

Laboratori de Neurofisiologia, Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.

AMPARs control fast synaptic communication between neurons and their function relies on auxiliary subunits, which importantly modulate channel properties. Although it has been suggested that AMPARs can bind to TARPs with variable stoichiometry, little is known about the effect that this stoichiometry exerts on certain AMPAR properties. Here we have found that AMPARs show a clear stoichiometry-dependent modulation by the prototypical TARP γ2 although the receptor still needs to be fully saturated with γ2 to show some typical TARP-induced characteristics (i.e. an increase in channel conductance). We also uncovered important differences in the stoichiometric modulation between calcium-permeable and calcium-impermeable AMPARs. Moreover, in heteromeric AMPARs, γ2 positioning in the complex is important to exert certain TARP-dependent features. Finally, by comparing data from recombinant receptors with endogenous AMPAR currents from mouse cerebellar granule cells, we have determined a likely presence of two γ2 molecules at somatic receptors in this cell type.
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http://dx.doi.org/10.7554/eLife.53946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299370PMC
May 2020

Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction.

Neuron 2018 10 23;100(1):91-105.e9. Epub 2018 Aug 23.

Hans-Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address:

AMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor subunits, providing a framework to explain disease symptoms.
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http://dx.doi.org/10.1016/j.neuron.2018.07.048DOI Listing
October 2018

Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.

Front Mol Neurosci 2018 8;11:275. Epub 2018 Aug 8.

Laboratori de Neurofisiologia, Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.

In neurons, AMPA receptor (AMPAR) function depends essentially on their constituent components:the ion channel forming subunits and ion channel associated proteins. On the other hand, AMPAR trafficking is tightly regulated by a vast number of intracellular neuronal proteins that bind to AMPAR subunits. It has been recently shown that the interaction between the GluA1 subunit of AMPARs and carnitine palmitoyltransferase 1C (CPT1C), a novel protein partner of AMPARs, is important in modulating surface expression of these ionotropic glutamate receptors. Indeed, synaptic transmission in CPT1C knockout (KO) mice is diminished supporting a positive trafficking role for that protein. However, the molecular mechanisms of such modulation remain unknown although a putative role of CPT1C in depalmitoylating GluA1 has been hypothesized. Here, we explore that possibility and show that CPT1C effect on AMPARs is likely due to changes in the palmitoylation state of GluA1. Based on analysis, Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity. When these residues are mutated or when PTE activity is inhibited, the CPT1C effect on AMPAR trafficking is abolished, validating the CPT1C catalytic triad as being responsible for PTE activity on AMPAR. Moreover, the histidine residue (His 470) of CPT1C is crucial for the increase in GluA1 surface expression in neurons and the H470A mutation impairs the depalmitoylating catalytic activity of CPT1C. Finally, we show that CPT1C effect seems to be specific for this CPT1 isoform and it takes place solely at endoplasmic reticulum (ER). This work adds another facet to the impressive degree of molecular mechanisms regulating AMPAR physiology.
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http://dx.doi.org/10.3389/fnmol.2018.00275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092487PMC
August 2018