Abstract
GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-gangliosidosis in a new Glb1 knockout mouse model. Glb1−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material GM1, GA1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.
Highlights
GM1-gangliosidosis is a lysosomal storage disease belonging to the sphingolipidoses caused by β-galactosidase (Glb1) deficiency [1]
Standard genotyping by PCR analysis on the Glb1 gene demonstrated a single band of 1171 base pairs in homozygous Glb1−/− mice, whereas a second band of 541 bp was present in heterozygous mice
Fibroblasts isolated from Glb1−/− mice aged two to six months, revealed a significantly decreased β-galactosidase activity (0.03 to 0.98 nmol/mg/min) compared to fibroblasts derived from WT control mice (3.69 to 7.91 nmol/mg/min; Figure 1)
Summary
GM1-gangliosidosis is a lysosomal storage disease belonging to the sphingolipidoses caused by β-galactosidase (Glb1) deficiency [1]. The infantile form (type 1) (OMIM# 230500) causes psychomotor disorders and seizures, damage to the central nervous system (CNS), hepatosplenomegaly, skeletal malformations, and early death during the first year of age. The late infantile or juvenile form (type 2) (OMIM#230600) manifests between seven months and three years of age, with CNS and psychomotor symptoms and seizures. This form progresses more slowly than the infantile one. The adult form (type 3) (OMIM# 230650) emerges late, and causes CNS disturbances including speech and walking disorders, as well as skeletal malformations [25,26].
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