Intermittent enzyme replacement therapy with recombinant human ß-galactosidase prevents neuraminidase 1 deficiency
J Biol Chem
; 295(39): 13556-13569, 2020 09 25.
Article
en En
| MEDLINE
| ID: mdl-32727849
ABSTRACT
Mutations in the galactosidase ß 1 (GLB1) gene cause lysosomal ß-galactosidase (ß-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. ß-Gal and neuraminidase 1 (NEU1) form a multienzyme complex in lysosomes along with the molecular chaperone, protective protein cathepsin A (PPCA). NEU1 is deficient in the neurodegenerative lysosomal storage disease sialidosis, and its targeting to and stability in lysosomes strictly depend on PPCA. In contrast, ß-Gal only partially depends on PPCA, prompting us to investigate the role that ß-Gal plays in the multienzyme complex. Here, we demonstrate that ß-Gal negatively regulates NEU1 levels in lysosomes by competitively displacing this labile sialidase from PPCA. Chronic cellular uptake of purified recombinant human ß-Gal (rhß-Gal) or chronic lentiviral-mediated GLB1 overexpression in GM1 gangliosidosis patient fibroblasts coincides with profound secondary NEU1 deficiency. A regimen of intermittent enzyme replacement therapy dosing with rhß-Gal, followed by enzyme withdrawal, is sufficient to augment ß-Gal activity levels in GM1 gangliosidosis patient fibroblasts without promoting NEU1 deficiency. In the absence of ß-Gal, NEU1 levels are elevated in the GM1 gangliosidosis mouse brain, which are restored to normal levels following weekly intracerebroventricular dosing with rhß-Gal. Collectively, our results highlight the need to carefully titrate the dose and dosing frequency of ß-Gal augmentation therapy for GM1 gangliosidosis. They further suggest that intermittent intracerebroventricular enzyme replacement therapy dosing with rhß-Gal is a tunable approach that can safely augment ß-Gal levels while maintaining NEU1 at physiological levels in the GM1 gangliosidosis brain.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Beta-Galactosidasa
/
Terapia de Reemplazo Enzimático
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Fibroblastos
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Lisosomas
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Mucolipidosis
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos