EEFSEC deficiency: A selenopathy with early-onset neurodegeneration.

Inborn errors of selenoprotein expression arise from deleterious variants in genes encoding selenoproteins or selenoprotein biosynthetic factors, some of which are associated with neurodegenerative disorders. This study shows that bi-allelic selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC) variants cause selenoprotein deficiency, leading to progressive neurodegeneration. EEFSEC deficiency, an autosomal recessive disorder, manifests with global developmental delay, progressive spasticity, ataxia, and seizures.

Structural Insights into the Iodothyronine Deiodinase 2 Catalytic Core and Deiodinase Catalysis and Dimerization.

Iodothyronine deiodinases (Dio) are selenocysteine-containing membrane enzymes that activate and inactivate the thyroid hormones (TH) through reductive iodide eliminations. The three deiodinase isoforms are homodimers sharing highly conserved amino acid sequences, but they differ in their regioselectivities for the deiodination reaction and regulatory features. We have now solved a crystal structure of the mouse deiodinase 2 (Dio2) catalytic domain.

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (HSePO), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY.

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance.

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6).

Identification of Human TRIAC Transmembrane Transporters.

3,5,3'-Triiodothyroacetic acid (TRIAC) is a T-receptor agonist pharmacologically used in patients to mitigate T resistance. It is additionally explored to treat some symptoms of patients with inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8, ). MCT8 is expressed along the blood-brain barrier, on neurons, astrocytes, and oligodendrocytes.