(Phospho)creatine: the reserve and merry-go-round of brain energetics

• Type of Material: Article
• Authors: Hong-Ru Chen, University of Virginia; Antonuis DeGrauw, Emory University; Chia-Yi Kuan, Emory University
• Language: English
• Date: 2023-02-01
• Publisher: WOLTERS KLUWER MEDKNOW PUBLICATIONS
• Publication Version: Final Published Version
• Copyright Statement: © Neural Regeneration Research
• License: Creative Commons Attribution-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.4103/1673-5374.346470
• Title of Journal or Parent Work: NEURAL REGENERATION RESEARCH
• Volume: 18
• Issue: 2
• Start Page: 327
• End Page: 328
• Grant/Funding Information: This work was supported by the NIH grant NS108763 (to CYK).
• Keywords: Life Sciences & Biomedicine; Science & Technology; Neurosciences; Cell Biology; Neurosciences & Neurology; AUTOPHAGY; CREATINE
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Creatine transporter (CrT)-deficiency, the most common form of the cerebral creatine deficiency syndromes, causes cognition impairments and severe reduction of the brain creatine (Cr) and phosphocreatine (PCr) levels, and responds poorly to oral Cr supplement as a treatment option. The causes of cognitive impairments in CrT-deficient children remain unclear. We recently use gene-targeting to create a mouse model of CrT-deficiency to assess the impacts of Cr/PCr deficiency on brain energetics and stress-adaptation responses (Chen et al., 2021). We found that Cr/PCr-deficiency impairs the development of dendritic spines and synapses, skews the balance of mechanistic target of rapamycin (mTOR) and autophagy signaling towards catabolism, and elevates the sensitivity to external stress, including ischemia or hypoxia, to cause greater brain injury. Notably, intranasal delivery of Cr after cerebral ischemia raises the brain Cr/PCr levels and reduces the infarct size in CrT-null mice, despite Cr itself lacking a high-energy phosphoryl group. These findings highlight a critical role of Cr/PCr for maintaining brain energetics and suggest potential therapies of CrT-deficiency.