Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: Similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III)

Björn Kowalewski, Peter Heimann, Theresa Ortkras, Renate Lüllmann-Rauch, Tomo Sawada, Steven U. Walkley, Thomas Dierks, Markus Damme

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12 Scopus citations


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 showthat Arsg KOmice share commonneuropathological 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.

Original languageEnglish (US)
Pages (from-to)1856-1868
Number of pages13
JournalHuman molecular genetics
Issue number7
Publication statusPublished - Oct 28 2014


ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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