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.

A theory inspired proposal for a novel medical treatment in autism. The cerebellar model of autism and the hypothesis of dorsal stream dysfunction: evidence from idiopathic and syndromic cases.

“…Neuropathological changes are largely restricted to the cerebellum and cell death was exclusively of Purkinje cells highlighting their exquisite susceptibility (Kowalewski et al 2015). The major neurological finding in these mice, ataxia is consistent with the anterior-to-posterior gradient of decreasing cell loss found.…”

The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

“…This approach has been previously reported by others and has been successful for finding mutations that cause NCL in dogs (Guo et al, , ; Gilliam et al, ). One of the genes ( ARSG ) considered as a candidate gene for NCL has now been reclassified as causative of a form of MPS IIIE (Kowalewski et al, , ). However, the close proximity of these neurodegenerative disorders made exclusion of a mutation in this gene important.…”

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

“…On the other hand, an NCL-like disorder in American Staffordshire Terriers that results from a mutation in ARSG was originally designated as an NCL, even though no known human form of NCL had been shown to result from mutations in this gene (Abitbol et al, 2010). Subsequent analyses using a transgenic mouse model led to the reclassification of the canine disorder to the group of lysosomal storage diseases known as mucopolysaccharidoses (Kowalewski et al, 2015; Kowalewski et al, 2012; Kowalewski et al, 2014). In addition, we evaluated Shiba Inu dogs that exhibited a progressive neurological disease and massive accumulation of autofluorescent storage material in brain, retina and heart similar to confirmed canine NCLs (Figs.…”