Abstract
GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).
Highlights
Glycoconjugates play a key role in cellular function and are tightly regulated both in terms of biosynthesis and catabolism. β-Galactosidase (β-GAL) is a lysosomal hydrolase that cleaves βlinked galactose residues from the non-reducing end of glycan moieties found in various glycoconjugates
Reduction in β-GAL activity leads to the accumulation of GM1 ganglioside and its asialo derivative GA1, primarily in lysosomes of neuronal tissue (Caciotti et al, 2011; Jarnes Utz et al, 2017)
In addition to the storage of GM1 ganglioside, other glycoconjugates with β-galactose at the non-reducing end are detectable in high concentration in patients’ urine, including N-linked glycans, and various O-linked glycans (Lawrence et al, 2019). These disease-related β-linked galactose-terminal oligosaccharides arise from the lysosomal breakdown of glycoproteins that are stored in the brain (Tsay and Dawson, 1976), liver (Holmes and O’Brien, 1978), and other biological fluids including urine (Brunetti-Pierri and Scaglia, 2008; Bruggink et al, 2012) and amniotic fluid (Piraud et al, 2017)
Summary
Glycoconjugates play a key role in cellular function and are tightly regulated both in terms of biosynthesis and catabolism. β-Galactosidase (β-GAL) is a lysosomal hydrolase that cleaves βlinked galactose residues from the non-reducing end of glycan moieties found in various glycoconjugates. In addition to the storage of GM1 ganglioside, other glycoconjugates with β-galactose at the non-reducing end are detectable in high concentration in patients’ urine, including N-linked glycans, and various O-linked glycans (Lawrence et al, 2019). These disease-related β-linked galactose-terminal oligosaccharides arise from the lysosomal breakdown of glycoproteins that are stored in the brain (Tsay and Dawson, 1976), liver (Holmes and O’Brien, 1978), and other biological fluids including urine (Brunetti-Pierri and Scaglia, 2008; Bruggink et al, 2012) and amniotic fluid (Piraud et al, 2017). The N-glycan metabolite A2G2 was proposed to be a surrogate glycan biomarker of GM1 gangliosidosis (Lawrence et al, 2019)
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