) Creatine (Cr) and its high-energy product phosphocreatine (PCr) are key components of the phosphagen system that, along with glycolysis, replenishes ATP to provide the fuels for proper cellular functions. The human body synthesizes approximately 50% of the daily need for Cr from arginine and glycine using arginine:glycine amidinotrasnferase (AGAT, in kidney) and guanidinoacetate methyltransferase (GAMT, in liver), and the other half of Cr is derived from food. While its subcellular localization remains unclear, creatine transporter (CrT) is essential for building/maintaining the brain Cr concentration in humans, which is clearly demonstrated in the disease CrT deficiency that was first discovered in 2001. In the absence of CrT (which is located in the X-chromosome), the afflicted children manifest severe cognitive deficits and near-complete absence of the brain Cr/PCr on magnetic resonance spectroscopy (MRS). Importantly, unlike patients with Cr synthesis enzyme mutations, those with CrT deficiency respond poorly to Cr supplement treatment. Hence, there is a need to determine the functions of CrT and the neuropathological basis of its deficiency in order to develop effective clinical treatments. Based on these results, we hypothesize that the absence of Cr/PCr promotes the AMPK and autophagic signaling pathways, while suppressing mTOR activity in the brain, leading to dendritic spine dysgenesis and susceptibility to hypoxic-ischemic injury. Further, CrT mediates the transport of Cr across pericytes and/or the astroglial end-feet in the brain. Finally, intranasal Cr application can restore the brain Cr/PCr level and correct neuropathological consequences of CrT deficiency. We will test these hypotheses in three specific aims.
Aim 1 : To determine the functions and sub-cellular location of CrT in the brain.
Aim 2 : To determine the impacts of CrT deficiency on cell signaling and cerebral ischemia.
Aim 3 : To develop treatments of the neuropathological and cognitive deficits in CrT deficiency.
): Creatine (Cr) is a crucial energy source in the brain, and it is delivered to brain or neurons by a specialized protein called creatine transporter (CrT). Approximately 42,000 males in the United States are affected by CrT mutation, in which creatine cannot enter the brain, leading to severe learning disabilities, autistic behaviors, recurring epileptic seizures, and needs for lifelong care. There is no therapy for CrT deficiency approved by the Food and Drug Administration (FDA). Thus, the NIH has designated CrT deficiency as a high priority in the ?Therapeutics for Rare and Neglected Diseases? (TRND) program to recognize the need for better understanding and effective treatment of this grave neurodevelopmental disorder.
