title: Aspartoacylase-lacZ knockin mice: an engineered model of Canavan disease.
abstract: Canavan Disease (CD) is a recessive leukodystrophy caused by loss of function mutations in the gene encoding aspartoacylase (ASPA), an oligodendrocyte-enriched enzyme that hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. The neurological phenotypes of different rodent models of CD vary considerably. Here we report on a novel targeted aspa mouse mutant expressing the bacterial β-Galactosidase (lacZ) gene under the control of the aspa regulatory elements. X-Gal staining in known ASPA expression domains confirms the integrity of the modified locus in heterozygous aspa lacZ-knockin (aspa(lacZ/+)) mice. In addition, abundant ASPA expression was detected in Schwann cells. Homozygous (aspa(lacZ/lacZ)) mutants are ASPA-deficient, show CD-like histopathology and moderate neurological impairment with behavioural deficits that are more pronounced in aspa(lacZ/lacZ) males than females. Non-invasive ultrahigh field proton magnetic resonance spectroscopy revealed increased levels of NAA, myo-inositol and taurine in the aspa(lacZ/lacZ) brain. Spongy degeneration was prominent in hippocampus, thalamus, brain stem, and cerebellum, whereas white matter of optic nerve and corpus callosum was spared. Intracellular vacuolisation in astrocytes coincides with axonal swellings in cerebellum and brain stem of aspa(lacZ/lacZ) mutants indicating that astroglia may act as an osmolyte buffer in the aspa-deficient CNS. In summary, the aspa(lacZ) mouse is an accurate model of CD and an important tool to identify novel aspects of its complex pathology.
authors.affiliation: Institute of Physiological Chemistry, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Mersmann
authors.forename: Dmitri
authors.initials: D
authors.lastname: Tkachev
authors.forename: Ruth
authors.initials: R
authors.lastname: Jelinek
authors.forename: Philipp Thomas
authors.initials: PT
authors.lastname: Röth
authors.forename: Wiebke
authors.initials: W
authors.lastname: Möbius
authors.forename: Torben
authors.initials: T
authors.lastname: Ruhwedel
authors.forename: Sabine
authors.initials: S
authors.lastname: Rühle
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weber-Fahr
authors.forename: Alexander
authors.initials: A
authors.lastname: Sartorius
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
mesh_terms: D000581:Amidohydrolases / Q000235:genetics*; D000818:Animals; D017825:Canavan Disease / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D007763:Lac Operon; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012727:Sex Characteristics
chemical_list: D000581:Amidohydrolases; C019751:aspartoacylase