SLC6 Transporter Folding Diseases and Pharmacochaperoning.

Mutations in solute carrier 6 (SLC6) family transporters cause misfolding and lead to diseases such as infantile dystonia (from dopamine transporter mutations), mental retardation (from creatine transporter mutations), and hyperekplexia (from glycine transporter mutations). Compounds that correct these folding defects, known as pharmacochaperones, were first discovered in serotonin transporter mutants, where ibogaine and its metabolite noribogaine were found to rescue folding-deficient mutants. Additional compounds have since been identified that restore function in dopamine transporter mutants. These agents not only offer therapeutic potential for affected children but also serve as tools to study transporter folding, potentially enabling the rational design of pharmacochaperones.

Study at a glance

Abstract

The human genome encodes 19 genes of the solute carrier 6 (SLC6) family; non-synonymous changes in the coding sequence give rise to mutated transporters, which are misfolded and thus cause diseases in the affected individuals. Prominent examples include mutations in the transporters for dopamine (DAT, SLC6A3), for creatine (CT1, SLC6A8), and for glycine (GlyT2, SLC6A5), which result in infantile dystonia, mental retardation, and hyperekplexia, respectively. Thus, there is an obvious unmet medical need to identify compounds, which can remedy the folding deficit. The pharmacological correction of folding defects was originally explored in mutants of the serotonin transporter (SERT, SLC6A4), which were created to study the COPII-dependent export from the endoplasmic reticulum. This led to the serendipitous discovery of the pharmacochaperoning action of ibogaine. Ibogaine and its metabolite noribogaine also rescue several disease-relevant mutants of DAT. Because the pharmacology of DAT and SERT is exceptionally rich, it is not surprising that additional compounds have been identified, which rescue folding-deficient mutants. These compounds are not only of interest for restoring DAT function in the affected children. They are also likely to serve as useful tools to interrogate the folding trajectory of the transporter. This is likely to initiate a virtuous cycle: if the principles underlying folding of SLC6 transporters are understood, the design of pharmacochaperones ought to be facilitated.