Recently, we described severe expressive and cognitive delays in a 6-year-old boy, who has a unique creatine (Cr) deficiency in the brain, which was diagnosed by proton magnetic resonance spectroscopy (MRS). Upon further analysis, we found that he has a nonsense mutation in the X-lined Cr transporter gene (CT1;SLC6A8), which resulted in the expression of a truncated (non-functional) Cr transporter protein. Since that study, four additional families have been recognized in Cincinnati with mutations in the X-linked Cr transporter gene and nearly 30 families worldwide. These patients all have mental retardation, severe expressive language disorder and mild epilepsy. Despite a growing body of knowledge about the Cr, Cr kinase and phosphocreatine system in the brain, there is no standardized method for improving brain function when the brain creatine transporter is deficient. What is clearly needed is a suitable animal model of this disease such that methods to get creatine across the blood brain barrier can be developed and tested. In this project we will develop a Cr transporter knockout mouse model, such that the efficacy of new treatment paradigms, drugs, and other therapies can be tested. For this research project, we propose to test the following hypotheses: 1) a mouse knockout of this Cr transport defect can model the human disease, and 2) that therapeutic strategies can be given to normalize brain function in these mice. This mouse knockout will model the Cr transporter defect we have discovered in that the brain will lack the ability to transport creatine across the blood brain barrier. To address Hypothesis 1, we will generate a Cr transporter knockout mouse. Cr levels will be determined in the brains of these mice and we will characterize the functional, and biochemical changes observed in Cr transporter knockout mice. Having an animal model that closely mirrors the human disease will enable adequate testing and development of therapies designed at getting creatine across the blood brain barrier and improving brain function. To address Hypothesis 2, the Cr transporter knockout mice and control mice will be treated with Cr formulations that may be capable of transporting creatine across the blood brain barrier and improve brain metabolism and cognitive function of the mice. The goal for Hypothesis 2 is to develop methods and drugs to improve brain energy metabolism by getting creatine into the brain.
| Kurosawa, Yuko; Degrauw, Ton J; Lindquist, Diana M et al. (2012) Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. J Clin Invest 122:2837-46 |
| Skelton, Matthew R; Schaefer, Tori L; Graham, Devon L et al. (2011) Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency. PLoS One 6:e16187 |
| Clark, Joseph F; Doepke, Amos; Filosa, Jessica A et al. (2006) N-acetylaspartate as a reservoir for glutamate. Med Hypotheses 67:506-12 |
| Cecil, Kim M (2006) MR spectroscopy of metabolic disorders. Neuroimaging Clin N Am 16:87-116, viii |
