GSE176188
Sodium phenylbutyrate rescues thyroid hormone transport in brain endothelial cells
Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease leading to a severe developmental delay. Some MCT8 deficient patients are not as severely affected than others due to residual thyroid hormone (TH) transport. Previously, we hypothesized that these patients' mutations destabilize the MCT8 protein, which consequently will be sent for degradation. We have already demonstrated that the chemical chaperone sodium phenylbutyrate (NaPB) rescues the function of these mutants by stabilizing their protein expression in an overexpressing cell system. Here we expand our previous work and used human iPSC-derived brain microvascular endothelial-like cells (iBMECs) as a model. We could show that NaPB rescues decreased mutant MCT8 expression and restores transport function. Furthermore, we identified MCT10 as another TH transporter that contributes to T3 uptake. The decrease in mutant protein expression could be explained by the activation of components of the unfolded protein response (UPR) machinery. Increased expression after NaPB treatment is a consequence of UPR attenuation and the stabilization of MCT8 mRNA. In conclusion, we demonstrate that NaPB is suitable to stabilize pathogenic missense mutations and activate transport function in a human-derived cell model opening the possibility of repurposing the FDA-approved drug NaPB for MCT8 deficiency. Overall design: 3' Poly(A) RNA-sequencing of N = 10 human BMEC with N = 2 of 5 different mutations in MCT8 (SLC16A2). Ribosome profiling  with N = 2 of 2 different  mutations and one mutation with Phenylbutyrate (2PB) treatment.