Are Astrocytes the Missing Link Between Lack of Brain Aspartoacylase Activity and the Spongiform Leukodystrophy in Canavan Disease?

Abstract

Canavan disease (CD) is a genetic degenerative brain disorder associated with mutations of the gene encoding aspartoacylase (ASPA). In humans, the CD syndrome is marked by early onset, hydrocephalus, macroencephaly, psychomotor retardation, and spongiform myelin sheath vacuolization with progressive leukodystrophy. Metabolic hallmarks of the disease include elevated N-acetylaspartate (NAA) levels in brain, plasma and CSF, along with daily excretion of large amounts of NAA and its anabolic metabolite, N-acetylaspartylglutamate (NAAG). Of the observed neuropathies, the most important appears to be the extensive demyelination that interferes with normal neuronal signaling. However, finding the links between the lacks of ASPA activity in oligodendrocytes, the buildup of NAA in white matter (WM) and the mechanisms underlying the edematous spongiform leukodystrophy have remained elusive. In this analytical review we consider what those links might be and propose that in CD, the pathological buildup of NAA in limited WM extracellular fluid (ECF) is responsible for increased ECF osmotic-hydrostatic pressure and initiation of the demyelination process. We also hypothesize that NAA is not directly liberated by neurons in WM as it is in gray matter, and that its source in WM ECF is solely as a product of the catabolism of axon-released NAAG at nodes of Ranvier by astrocyte NAAG peptidase after it has docked with the astrocyte surface metabotropic glutamate receptor 3. This hypothesis ascribes for the first time a possible key role played by astrocytes in CD, linking the lack of ASPA activity in myelinating oligodendrocytes, the pathological buildup of NAA in WM ECF, and the spongiform demyelination process. It also offers new perspectives on the cause of the leukodystrophy in CD, and on possible treatment strategies for this inherited metabolic disease.

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

“…Nevertheless, in accordance with the molecular water pump theory that NAA functions as an osmolyte, it was hypothesized that astrocytes play a role in CD via increased N-acetylaspartylglutamate (NAAG) and its interaction with astrocytic glutamate receptors and subsequent extracellular breakdown of NAAG and liberation of NAA, leading to osmotic shifts and intracerebral water accumulation (40). Following the paradigm of oligodendroglial ASPA, gene replacement therapy for CD has focused on ASPA restoration in oligodendrocytes.…”

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

“…Recently, it was shown that defective survival and differentiation of immature oligodendrocytes may also be implicated in CD ( 108 ). Furthermore, the toxic effects of NAA in myelin vacuolization should not be neglected ( 109 ).…”

Non-genetic therapeutic approaches to Canavan disease

“…Although the intracerebral NAA accumulation and dysmyelination appear to be the major regulators of the disease's progress and phenotype, experimental evidence 7 GRM3 and NAAG-peptidase are actually a complex reported to appear particularly in the white matter astrocytic cells (Baslow, 2008;Baslow and Guilfoyle, 2009;Fotuhi et al, 1994).…”

“…It has been suggested to prevent NAA release from neurons or increase expulsion from the CNS by affecting blood-brain barrier (BBB) permeability ). An alternative mechanism that could be targeted is inhibition of the NAA synthetic pathways (Baslow and Guilfoyle, 2009). The latter could either be accomplished by competitive or irreversible inhibition of aspartate N-acetyltransferase (AspNAT; the enzyme that synthesises NAA from Asp and Acetyl-CoA) (Figure 1.c) or by inhibiting NAAGpeptidase in order to prevent NAA synthesis from NAAG hydrolysis; the latter is further discussed below.…”

“…Considering the hypothesis that an important amount of NAA accumulating within the white matter of CD patients could derive from NAAG catabolism, Baslow and Guilfoyle (2009) have suggested that the use of NAAG-peptidase inhibitors or of metabotropic glutamate receptor 3 (GRM3 or mGluR3; the natural astrocytic surface target for NAAG) 7 agonists and antagonists (Baslow, 2008) could slow down the dysmyelination process.…”