Skip to main content

Proteomic analysis of MCT8 knockout and knockdown human iPSCs

Project Member(s): Santos, J., Milthorpe, B., Padula, M.

Funding or Partner Organisation: The Trustee for Sherman Foundation

Start year: 2016

Summary: Point mutations in the gene encoding the cell-membrane thyroid hormone T3 transporter protein monocarboxylic acid transporter 8 (MCT8) or solute carrier family 16 member 2 (SLC16A2) manifests phenotypically in only male patients as severe neuronal developmental deficiencies at infancy. These deficiencies range in severity according to the site of mutation in the associated transporter and symptoms include neurodevelopmental abnormalities which manifest as cognitive deficits, infantile hypotonia, diminished muscle mass and generalized muscle weakness, progressive spastic quadriplegia, joint contractures, and dystonic and/or athetoid movement(1). This developmental delay occurs due to the inability of the requisite hormone T3 to access neuronal cells thus postponing their maturation to myelinated neurons. The availability of induced pluripotent stem cells (iPSCs) from the patients would serve as prime candidates for an in vitro study of the effect of T3 analogues treatment and/or ABCD2 gene expression. The iPSCs have been widely shown to be transdifferentiated into multilineage neuronal cells in controlled conditions, these including myelin sheath forming neurons, oligodentrocytes and astroctyes. This project attempts to utilise current iPSC neuronal differentiation and proteomic techniques to elucidate the mechanisms involved in the DITPA; TRIAC or TETRAC treatment of human iPSCs with the MCT8 mutation relative to normal cells. A proteomic investigation to identify the up regulation of membrane associated transport proteins which translocate the compound is vital in understanding the movement and interaction of these compounds with the target cells. Furthermore the neuronal markers, such as NF200, parvalbumin, calbindin and synaptobrevin which are diminished in MCT8 mutant samples are hypothesised to return to normal expression levels .

Keywords: Stem cells, iPSCs, Allan-Herndon-Dudley-Syndrome, Drug discovery, proteomics, interaction networks

FOR Codes: Proteomics and Intermolecular Interactions (excl. Medical Proteomics), Systems Biology, Nervous System and Disorders, Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified, Clinical health