α-Galactosidase A Knockout Mice

Abstract

Fabry disease is an X-linked lysosomal storage disease caused by deficient activity of α-galactosidase A and the resultant systemic accumulation of globotrioasylceramide (GL-3) and related glycolipids. α-Galactosidase A gene knockout (Gla KO) mice have no α-galactosidase A activity and progressively accumulate GL-3 in tissues and fluids, similarly to FD patients. The nature and temporal effects of the progressive substrate accumulation on tissue histology in these mice have not previously been characterized. Here, we report the pathology of young to old (3 to 17 months old) Gla KO mice and compare these changes with those in strain-matched control animals. Gla KO mice accumulated GL-3 in various tissues and fluids with age. Lysosomal GL-3 inclusions increased with age in multiple cell types, including renal epithelial, intestinal, and vascular smooth muscle cells, and neurons in trigeminal and dorsal root ganglia, as detected by light and electron microscopy. However, unlike the case for male FD patients with the type 1 classic phenotype, GL-3 inclusions were not detected in vascular endothelial cells or cardiomyocytes. The histological changes in Gla KO mice better resemble the type 2 later-onset phenotype observed in patients with residual α-galactosidase A activity. GL-3 accumulation in the small intestine and sensory ganglia of Gla KO mice provides a model for study of enteropathy and neuropathy in Fabry disease.

Comprehensive and differential long-term characterization of the alpha-galactosidase A deficient mouse model of Fabry disease focusing on the sensory system and pain development

“… 15 In a recent study, the same group investigated a different type of α-GAL-deficient mice 16 from 3 to 17 months of age and compared heat withdrawal latencies in the hot plate test with non-littermate 129S6/SvEvTac mice and without gender differentiation. 17 The authors report increased heat withdrawal latencies in these α-GAL ko mice 16 from the age of 3 months with a further increase at 12 to 17 months. 17 …”

“… 17 The authors report increased heat withdrawal latencies in these α-GAL ko mice 16 from the age of 3 months with a further increase at 12 to 17 months. 17 …”

Electrocardiographic Changes and Arrhythmia in Fabry Disease

“…As enzyme replacement therapy is available, earliest possible recognition and treatment of these patients and family members is of utmost importance. Although substantial progresses have been made in the past years studying histopathological changes associated with Gb3 accumulation in animal model studies using GLA-knock-out mice, they remain, for the time being, of limited value for Fabry disease-associated cardiomyopathy, since they lack of lysosomal Gb3 storage in vascular endothelial cells and cardiomyocytes ( 42 ).…”

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

“…Several α-GLA animal models have been generated to better understand Fabry disease pathogenesis [60][61][62][63]. Among them, one Gla knock-out model, also overexpressing the Gb3 synthase, developed a significant neurological phenotype characterized by spontaneous tremors, slowed movements and gait disturbances [64].…”