The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome

Abstract

Creatine provides cells with high-energy phosphates for the rapid reconstitution of hydrolyzed adenosine triphosphate. The eponymous creatine transporter (CRT1/SLC6A8) belongs to a family of solute carrier 6 (SLC6) proteins. The key role of CRT1 is to translocate creatine across tissue barriers and into target cells, such as neurons and myocytes. Individuals harboring mutations in the coding sequence of the human CRT1 gene develop creatine transporter deficiency (CTD), one of the pivotal underlying causes of cerebral creatine deficiency syndrome. CTD encompasses an array of clinical manifestations, including severe intellectual disability, epilepsy, autism, development delay, and motor dysfunction. CTD is characterized by the absence of cerebral creatine, which implies an indispensable role for CRT1 in supplying the brain cells with creatine. CTD-associated variants dramatically reduce or abolish creatine transport activity by CRT1. Many of these are point mutations that are known to trigger folding defects, leading to the retention of encoded CRT1 proteins in the endoplasmic reticulum and precluding their delivery to the cell surface. Misfolding of several related SLC6 transporters also gives rise to detrimental pathologic conditions in people; e.g., mutations in the dopamine transporter induce infantile parkinsonism/dystonia, while mutations in the GABA transporter 1 cause treatment-resistant epilepsy. In some cases, folding defects are amenable to rescue by small molecules, known as pharmacological and chemical chaperones, which restore the cell surface expression and transport activity of the previously non-functional proteins. Insights from the recent molecular, animal and human case studies of CTD add toward our understanding of this complex disorder

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

“…Future work will aim at further characterizing the molecular mechanism and the consequences of CTD in the Slc6a8 Y389C rat line both in periphery and in CNS. Recent work demonstrated that several variants of CrT are expressed although misfolded, some of them being rescued with chemical chaperones thus opening new avenues for the treatment of CTD patients 53 , 54 . Using the Slc6a8 Y389C rat line to develop new strategies of treatment for CTD, this chaperone approach will also be tested in this new in vivo model.…”

The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

“…Finally, Cr is critical to promote antitumor activity in the cytotoxic T CD8 + cells, and the response to tumor challenge is severely impaired in KO(2-4) mice [183]. These results add up to the accumulating evidence that implicates CRT in cancer, encouraging a close survey of cancer incidence in CTD patients [128].…”

“…Although locomotor activity was slightly increased in Nes-KO animals, it is unlikely that moderate hyperactivity could account for the observed cognitive dysfunction [102,125,126]. On the other hand, hyperactivity and attention deficits are commonly described in CTD patients [25,128]. Since hyperactivity in ubiquitous KO mice is presumably masked by the motor problems due to peripheral Cr deficiency, the presence of this phenotype in conditional mice represents an original finding, making them a viable model to study certain aspects of this disorder.…”

A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation

“…Conformational changes of the CRT might trigger quality control mechanisms involving N-glycosylation (e.g., unfolded protein response) [ 191 ]. For a recent comprehensive review on this topic and novel therapeutic strategies related to Cr deficiency syndrome, please refer to [ 192 ].…”