title: Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III).
abstract: Deficiency of arylsulfatase G (ARSG) leads to a lysosomal storage disease in mice resembling biochemical and pathological features of the mucopolysaccharidoses and particularly features of mucopolysaccharidosis type III (Sanfilippo syndrome). Here we show that Arsg KO mice share common neuropathological findings with other Sanfilippo syndrome models and patients, but they can be clearly distinguished by the limitation of most phenotypic alterations to the cerebellum, presenting with ataxia as the major neurological finding. We determined in detail the expression of ARSG in the central nervous system and observed highest expression in perivascular macrophages (which are characterized by abundant vacuolization in Arsg KO mice) and oligodendrocytes. To gain insight into possible mechanisms leading to ataxia, the pathology in older adult mice (>12 months) was investigated in detail. This study revealed massive loss of Purkinje cells and gliosis in the cerebellum, and secondary accumulation of glycolipids like GM2 and GM3 gangliosides and unesterified cholesterol in surviving Purkinje cells, as well as neurons of some other brain regions. The abundant presence of ubiquitin and p62-positive aggregates in degenerating Purkinje cells coupled with the absence of significant defects in macroautophagy is consistent with lysosomal membrane permeabilization playing a role in the pathogenesis of Arsg-deficient mice and presumably Sanfilippo disease in general. Our data delineating the phenotype of mucopolysaccharidosis IIIE in a mouse KO model should help in the identification of possible human cases of this disease.
authors.affiliation: Department of Chemistry, Biochemistry I, Bielefeld University, 33615 Bielefeld, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Kowalewski
authors.affiliation: Molecular Neurobiology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heimann
authors.affiliation: Department of Chemistry, Biochemistry I, Bielefeld University, 33615 Bielefeld, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Ortkras
authors.affiliation: Anatomical Institute, University of Kiel, D-24098 Kiel, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: The Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Tomo
authors.initials: T
authors.lastname: Sawada
authors.affiliation: The Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.affiliation: Department of Chemistry, Biochemistry I, Bielefeld University, 33615 Bielefeld, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dierks
authors.affiliation: Department of Chemistry, Biochemistry I, Bielefeld University, 33615 Bielefeld, Germany, mdamme@biochem.uni-kiel.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Damme
mesh_terms: D000818:Animals; D001192:Arylsulfatases / Q000172:deficiency* / Q000235:genetics; D001259:Ataxia / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000378:metabolism; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009084:Mucopolysaccharidosis III / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011689:Purkinje Cells / Q000378:metabolism
chemical_list: D006017:Glycolipids; C000593694:arylsulfatase G, mouse; D001192:Arylsulfatases