title: Astroglial redistribution of aquaporin 4 during spongy degeneration in a Canavan disease mouse model.
abstract: Canavan disease is a spongiform leukodystrophy caused by an autosomal recessive mutation in the aspartoacylase gene. Deficiency of oligodendroglial aspartoacylase activity and a subsequent increase of its substrate N-acetylaspartate are the etiologic factors for the disease. N-acetylaspartate acts as a molecular water pump. Therefore, an osmotic-hydrostatic mechanism is thought to be involved in the development of the Canavan disease phenotype. Astrocytes express water transporters and are critically involved in regulating and maintaining water homeostasis in the brain. We used the ASPA(Nur7/Nur7) mouse model of Canavan disease to investigate whether a disturbance of water homeostasis might be involved in the disease's progression. Animals showed an age-dependent impairment of motor performance and spongy degeneration in various brain regions, among the basal ganglia, brain stem, and cerebellar white matter. Astrocyte activation was prominent in regions which displayed less tissue damage, such as the corpus callosum, cortex, mesencephalon, and stratum Purkinje of cerebellar lobe IV. Immunohistochemistry revealed alterations in the cellular distribution of the water channel aquaporin 4 in astrocytes of ASPA(Nur7/Nur7) mice. In control animals, aquaporin 4 was located exclusively in the astrocytic end feet. In contrast, in ASPA(Nur7/Nur7) mice, aquaporin 4 was located throughout the cytoplasm. These results indicate that astroglial regulation of water homeostasis might be involved in the partial prevention of spongy degeneration. These observations highlight aquaporin 4 as a potential therapeutic target for Canavan disease.
authors.affiliation: Institute of Neuroanatomy, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany, tclarner@ukaachen.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Clarner
authors.forename: Nicola
authors.initials: N
authors.lastname: Wieczorek
authors.forename: Barbara
authors.initials: B
authors.lastname: Krauspe
authors.forename: Katharina
authors.initials: K
authors.lastname: Jansen
authors.forename: Cordian
authors.initials: C
authors.lastname: Beyer
authors.forename: Markus
authors.initials: M
authors.lastname: Kipp
mesh_terms: D000581:Amidohydrolases / Q000235:genetics; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017825:Canavan Disease / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D014867:Water / Q000378:metabolism
chemical_list: D051401:Aquaporin 4; D014867:Water; D000581:Amidohydrolases; C019751:aspartoacylase