Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation

J Mol Neurosci. 2003;21(3):185-90. doi: 10.1385/jmn:21:3:185.

Abstract

N-acetyl-L-aspartate (NAA), an abundant amino acid present in the vertebrate brain, is synthesized and stored primarily in neurons. Its metabolism is also dynamic, with NAA turning over more than once each day by its regulated efflux into extracellular fluid (ECF), cycling between an anabolic L-aspartate acetylating compartment in neurons and a catabolic NAA deacetylating compartment in oligodendrocytes. An inborn error in NAA metabolism results in Canavan disease (CD), a rare and usually fatal early-onset autosomal recessive human central nervous system (CNS) disease, caused by failure of the catabolic metabolism of NAA resulting from a lack of sufficient amidohydrolase II activity in oligodendrocytes. Various hypotheses regarding the metabolism of NAA and its role have been considered, and although NAA may perform several functions in the CNS, an important role of NAA appears to be osmoregulatory. Based on this role, an osmotic-hydrostatic mechanism for the etiology of the CD phenotype is proposed. In CD, the daily addition of 13375 Pascals (0.132 atmospheres or 1.94 lbs per square inch) of hydrostatic pressure to brain ECF, on the brain cell side of brain-barrier epithelial membranes, resulting from the continuous synthesis and efflux of NAA, is considered to be responsible for the syndrome.

Publication types

  • Review

MeSH terms

  • Animals
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / metabolism*
  • Brain / cytology
  • Brain / metabolism*
  • Canavan Disease / etiology
  • Canavan Disease / metabolism*
  • Canavan Disease / physiopathology
  • Extracellular Fluid / metabolism*
  • Humans
  • Hydrostatic Pressure / adverse effects
  • Membrane Transport Proteins / physiology*
  • Neurons / metabolism
  • Oligodendroglia / metabolism
  • Water-Electrolyte Balance / physiology

Substances

  • Membrane Transport Proteins
  • Aspartic Acid
  • N-acetylaspartate