A mouse model for the human lysosomal disease aspartylglycosaminuria

Abstract

Aspartylglycosaminuria (AGU), the most common disorder of glycoprotein degradation in humans, is caused by mutations in the gene encoding the lysosomal enzyme glycosylasparaginase (Aga). The resulting enzyme deficiency allows aspartylglucosamine (GlcNAc-Asn) and other glycoasparagines to accumulate in tissues and body fluids, from early fetal life onward. The clinical course is characterized by normal early development, slowly progressing to severe mental and motor retardation in early adulthood. The exact pathogenesis of AGU in humans is unknown and neither therapy nor an animal model for this debilitating and ultimately fatal disease exists. Through targeted disruption of the mouse Aga gene in embryonic stem cells, we generated mice that completely lack Aga activity. At the age of 5-10 months a massive accumulation of GlcNAc-Asn was detected along with lysosomal vacuolization, axonal swelling in the gracile nucleus and impaired neuromotor coordination. A significant number of older male mice had massively swollen bladders, which was not caused by obstruction, but most likely related to the impaired function of the nervous system. These findings are consistent with the pathogenesis of AGU and provide further data explaining the impaired neurological function in AGU patients.

Protein kinase CKIIα interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells

“…To examine if we could detect complex formation between endogenous CKIIa and Bcr, we prepared lysates from mouse brain, a relatively abundant source of Bcr protein (Fioretos et al, 1995;Kaartinen et al, 2001) and also known to express CKIIa . We then immunoprecipitated CKIIa protein from the lysates, and examined the precipitate for the presence of Bcr.…”

Activity of the Bcr GTPase-activating Domain Is Regulated through Direct Protein/Protein Interaction with the Rho Guanine Nucleotide Dissociation Inhibitor

“…Null mutant mice lacking Abr, Bcr, or both have been used to demonstrate that these two proteins are important negative regulators of activated Rac in cells of the innate immune system (22). In vivo, Bcr and Abr also regulate Rac functions in other organs, including the inner ear and cerebellum (23,24).…”

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

“…For example, a-mannosidosis (OMIM 248500), caused by mutations in the a-mannosidase (MAN2B1, EC 3.2.1.24, 609458) gene, has been described in cats, cattle, guinea pigs, humans, and knockout mice (Auclair and Hopwood 2007;Blanz et al 2008;Crawley and Walkley 2007;Damme et al 2011;Stinchi et al 1999;Vite et al 2001) and has somewhat different neurological manifestations and neuropathological characteristics depending on the species. Aspartylglucosaminuria (AGU, OMIM 208400) (Dunder et al 2010;Jalanko et al 1998;Kaartinen et al 1996) is caused by mutations in the gene for glycosylasparaginase (AGA, EC 3.5.1.26, 613228), the enzyme necessary for hydrolysis of the proteinoligosaccharide linkage in N-linked glycoproteins. Glycosylasparaginase deficiency results in accumulation of glycoasparagines, such as aspartylglucosamine (GlcNAc-Asn), a small molecule that may be analogous to Man(b1-4)GlcNAc.…”

“…Glycosylasparaginase deficiency results in accumulation of glycoasparagines, such as aspartylglucosamine (GlcNAc-Asn), a small molecule that may be analogous to Man(b1-4)GlcNAc. In the AGU mouse model (Jalanko et al 1998;Kaartinen et al 1996), CNS vacuolation is prominent in neurons and astrocytes of cortical and subcortical gray matter. Further understanding of the different patterns of pathology may lead to delineation of specific metabolic characteristics of subsets of neurons that are not currently understood.…”