Metabolic Changes in the Knockout Mouse for Canavan's Disease

Abstract

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency, which leads to accumulation of N-acetylaspartic acid in the brain and blood and an elevated level of N-acetylaspartic acid in the urine. The brain of patients with Canavan's disease shows spongy degeneration. How the enzyme deficiency and elevated N-acetylaspartic acid cause the pathophysiology observed in Canavan's disease is not obvious. The creation of a knockout mouse for Canavan's disease is being used as a tool to investigate metabolic pathways in the mouse and correlate them with the patients with Canavan's disease. The level of glutamate is lower in the knockout mouse brain than in the wild-type mouse brain, similar to what we have found in children with Canavan's disease, and so are the levels of gamma-aminobutyric acid (GABA). The level of aspartate is higher in the Canavan's disease mouse brain. The activity of aspartate aminotransferase, an enzyme involved in the malate-aspartate shuttle, is lower in the Canavan's disease mouse brain. The lower weight of the Canavan's disease mouse was in direct proportion to low total-body fat and bone mineral density. These changes might be similar to what is seen in patients with Canavan's disease and could have therapeutic implications.

Identification of quantitative trait transcripts for growth traits in the large scales of liver and muscle samples

“…The ASPA gene has been reported to be associated with growth in mice and humans. Adipocyte-specific genetic deletion of ASPA gene in mice reduces body weight (30,31,43). In the present study, the expression of ASPA gene was significantly associated with BodyWt_D210 (P ϭ 8.18E-05, r ϭ 0.195) and BodyWt_D240 (P ϭ 2.33E-04, r ϭ 0.153).…”

Severity of experimental traumatic brain injury modulates changes in concentrations of cerebral free amino acids

“…As this phenomenon is confined to sTBI only, it can be postulaed that, under pathological conditions causing imbalance of NAA homeostasis with a net decrease in its cerebral concentration below a given threshold value (lower than the lowest value recorded in mTBI rats), an increase in Asp can trigger its transamination into Glu by aminotransferase, significantly concurring to cause an increase in Glu concentrations. To corroborate this hypothesis, it should be underlined that significantly lower values of Glu are present in the brain of rats affected by experimental Canavan disease 46, 47, the rare inborn error of metabolism caused by defects in the enzyme ( N ‐acetylaspartoacylase) degrading NAA into Asp and acetate 48. Under these pathological conditions, NAA is not hydrolysed by oligodendrocytes thus decreasing brain Asp availability, in turn producing about 50% lower Glu value 46, 47.…”

“…To corroborate this hypothesis, it should be underlined that significantly lower values of Glu are present in the brain of rats affected by experimental Canavan disease [46,47], the rare inborn error of metabolism caused by defects in the enzyme (N-acetylaspartoacylase) degrading NAA into Asp and acetate [48]. Under these pathological conditions, NAA is not hydrolysed by oligodendrocytes thus decreasing brain Asp availability, in turn producing about 50% lower Glu value [46,47]. That is, brain Glu metabolism is, at in lest in part, linked to the turnover rate of NAA.…”

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

“…We postulate a metabolic sink theory for CD in which reduction of NAA levels independent of the metabolizing glial cell type is therapeutic, since neuronal expression of ASPA has been shown to have limited therapeutic effect (32). This theory implies that either a compensating mechanism for oligodendroglial NAA exists as inferred from the work of others (41,42) or the function of NAA can be rerouted to astrocytes to provide essential metabolites to oligodendrocytes (43). Given the metabolic connections among glial cells, it would not be surprising if metabolic support is not only provided from glia to neurons but also among glial cells, potentially establishing the NAA metabolism in astrocytes to provide aspartate and acetate to oligodendrocytes (44).…”