Rescuing Canavan Disease By Redirecting Metabolic Processing: Support For the Astrocyte Hypothesis of Canavan Disease Generation and A Possible Human Cure - Rescuing Canavan Disease By Redirecting Metabolic Processing: Support For the Astrocyte Hypothesis of Canavan Disease Generation and A Possible Human Cure - Open Access Pub

Canavan disease (CD) is a globally occurring but rare human spongiform leukodystrophy that is associated with inborn errors affecting the activity of aspartoacylase (ASPA), an enzyme highly expressed in oligodendrocytes that hydrolyzes N-acetylaspartate (NAA). Lack of ASPA activity is associated with the inability of oligodendrocytes to build or maintain axon-enveloping myelin sheaths. The primary source of NAA in brain is neurons, cells that synthesize but cannot catabolize it. Neurons also synthesize N-acetylaspartylglutamate (NAAG) from NAA and glutamate but cannot catabolize this substance as well. For their metabolism, these substances are released to extracellular fluid and are metabolized by oligodendrocyte ASPA and astrocyte NAAG peptidase respectively. A hypothesis developed suggested that the cause of the leukodystrophy component in CD was due to release of NAAG by neurons at white matter nodes of Ranvier, its catabolism by astrocytes forming NAA and increased osmotic-hydrostatic pressure as a result of its buildup at these nodes due to the lack of ASPA activity. In this communication, we provide evidence supporting this hypothesis and comment on the cause and possible cure for human CD. DOI10.14302/issn.2572-5424.jgm-17-1482 Rescuing Canavan Disease We bring attention to a recent study 1 in which a human adeno-associated virus genetic aspartoacylase (ASPA) construct was serendipitously inserted into the “wrong” cell and by redirecting its metabolic processing rescued a murine model of Canavan disease (CD). After achieving an overall cure including enhanced motor performance, these authors were prompted to “hypothesize” that ASPA expression in a non-oligodendrocyte glial cell, astrocytes, might be involved. This was subsequently ascertained using appropriate cell markers. In this communication, we provide metabolic, physiological and cellular contexts as well as a plausible mechanism for evaluating this remarkable finding. The Nature of Canavan Disease CD is an autosomal recessive disease due to inborn errors resulting from more than 100 different mutations in which oligodendrocyte expressed ASPA is inactive 1, 2, 3. CD is a rare disease in that there are only several hundred human cases worldwide at any given time. Spatially, it is distributed among all races of the world, but is especially prevalent in the Ashkenazi Jewish population of northern Russia. ASPA and N-acetyl-L-aspartate (NAA), its natural substrate synthesized by neurons and maintained at high mM levels in both gray matter (GM) and white matter (WM), are clearly important for