| First Author | Luu AR | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 39 | Pages | 13556-13569 |
| PubMed ID | 32727849 | Mgi Jnum | J:297420 |
| Mgi Id | MGI:6477820 | Doi | 10.1074/jbc.RA119.010794 |
| Citation | Luu AR, et al. (2020) Intermittent enzyme replacement therapy with recombinant human beta-galactosidase prevents neuraminidase 1 deficiency. J Biol Chem 295(39):13556-13569 |
| abstractText | Mutations in the galactosidase beta 1 (GLB1) gene cause lysosomal beta-galactosidase (beta-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. beta-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, beta-Gal only partially depends on PPCA, prompting us to investigate the role that beta-Gal plays in the multienzyme complex. Here, we demonstrate that beta-Gal negatively regulates NEU1 levels in lysosomes by competitively displacing this labile sialidase from PPCA. Chronic cellular uptake of purified recombinant human beta-Gal (rhbeta-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 rhbeta-Gal, followed by enzyme withdrawal, is sufficient to augment beta-Gal activity levels in GM1 gangliosidosis patient fibroblasts without promoting NEU1 deficiency. In the absence of beta-Gal, NEU1 levels are elevated in the GM1 gangliosidosis mouse brain, which are restored to normal levels following weekly intracerebroventricular dosing with rhbeta-Gal. Collectively, our results highlight the need to carefully titrate the dose and dosing frequency of beta-Gal augmentation therapy for GM1 gangliosidosis. They further suggest that intermittent intracerebroventricular enzyme replacement therapy dosing with rhbeta-Gal is a tunable approach that can safely augment beta-Gal levels while maintaining NEU1 at physiological levels in the GM1 gangliosidosis brain. |
