Cognitive function in hypothyroidism: what is that deiodinase again?

Abstract

Treatment of hypothyroidism involves the endogenous conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) and may not be optimal in some cases when based on T4 alone. In the current issue of the JCI, Jo et al. present results that explain the reduced enzymatic activity of a common genetic variant of the enzyme responsible for this conversion, type 2 deiodinase (DIO2). The authors further explore the functional consequences of this variant on brain T3 activity, endoplasmic reticulum stress in glial cells, and cognitive function. These findings have important implications for the clinical treatment of hypothyroidism and for susceptibility to other neurological and metabolic diseases.

Figure 1. Pathological basis of Ala92-DIO2.

Thr92-DIO2 localizes in the ER where, with the support of appropriate cofactors, it is able to convert T4 into T3 for transcriptional regulation in the nucleus. DIO2 is recycled through the Golgi. Ala92-DIO2 causes ER stress and impairs the recycling of DIO2, which aberrantly accumulates in the Golgi, where it is not active. ER stress and decreased T3 production exert biological effects on glial cells and neurons, affecting neurological function.