Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease

Abstract

Genetic mutations that severely diminish the activity of aspartoacylase (ASPA) result in the fatal brain dysmyelinating disorder, Canavan disease. There is no effective treatment. ASPA produces free acetate from the concentrated brain metabolite, N-acetylaspartate (NAA). Because acetyl coenzyme A is a key building block for lipid synthesis, we postulated that the inability to catabolize NAA leads to a brain acetate deficiency during a critical period of CNS development, impairing myelination and possibly other aspects of brain development. We tested the hypothesis that acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of Canavan disease. Glyceryltriacetate (GTA) was administered orally to tremor rats starting 7 days after birth, and was continued in food and water after weaning. Motor function, myelin lipids, and brain vacuolation were analyzed in GTA-treated and untreated tremor rats. Significant improvements were observed in motor performance and myelin galactocerebroside content in tremor rats treated with GTA. Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance. We also examined the expression of the acetyl coenzyme A synthesizing enzyme acetyl coenzyme A synthase 1 and found upregulation of expression in tremor rats, with a return to near normal expression levels in GTA-treated tremor rats. These results confirm the critical role played by NAA-derived acetate in brain myelination and development, and demonstrate the potential usefulness of acetate therapy for the treatment of Canavan disease.

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

“…Changes in neuronal tissues are limited, also because of the inability to reverse developmental defects, although striking behavioral improvements involving both CNS and PNS functioning were found ( 44,45,154 ). In a rodent model for CD, glyceryltriacetate supplementation was recently reported to improve motor performance and myelin lipid content ( 155 ). In Zellweger patients, alkyl-glycerol supplementation to rescue plasmalogen defi ciency has been performed with only little success ( 156 ), which may be related to the other peroxisomal defects that are not related to plasmalogen defi ciency in these patients.…”

Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease

“…Therapeutically, non-gene therapy strategies to reduce NAA or to recover myelination have failed to show substantial improvement in animal models or in patients and remain experimental (28)(29)(30). Preclinical gene therapy with rAAV2 and intracranial delivery strategies have also failed to effectively rescue the disease phenotype (31,32).…”

Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

“…7,8 High-energy phosphates, 9,10 coenzyme A metabolites, 11 ATP catabolites, 11 and neurotransmitters, 12,13 are some of the substances whose concentrations are temporarily affected as a result of a traumatic insult. Of particular relevance is the finding that N-acetylaspartate (NAA), an abundant brain-specific compound involved in several relevant biological functions including water homeostasis 14 and lipid myelin biosynthesis, 15 clearly mirrors TBI-induced changes in ATP, showing the same pattern of decrease and recovery following mTBI and no recovery in severe TBI or repeat mTBIs. 8,10,11 The strict correlation between NAA and ATP ensures that this compound may be used as a valid surrogate marker to monitor cerebral energy metabolism.…”