Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I.

Rosario Mosca,Laura Canafoglia,Yvan Campos,Leigh E Fremuth,Emil Kakkis,Simona Allievi,Jaclyn Cadaoas,Cynthia Tifft,Ida Annunziata,Vish Koppaka,Camilo Toro,Cinzia Gellera,Alessandra D’Azzo,Gepke Visser,Diantha Van De Vlekkert

doi:10.3390/jcm9030695

Abstract

Congenital deficiency of the lysosomal sialidase neuraminidase 1 (NEU1) causes the lysosomal storage disease, sialidosis, characterized by impaired processing/degradation of sialo-glycoproteins and sialo-oligosaccharides, and accumulation of sialylated metabolites in tissues and body fluids. Sialidosis is considered an ultra-rare clinical condition and falls into the category of the so-called orphan diseases, for which no therapy is currently available. In this study we aimed to identify potential therapeutic modalities, targeting primarily patients affected by type I sialidosis, the attenuated form of the disease. We tested the beneficial effects of a recombinant protective protein/cathepsin A (PPCA), the natural chaperone of NEU1, as well as pharmacological and dietary compounds on the residual activity of mutant NEU1 in a cohort of patients’ primary fibroblasts. We observed a small, but consistent increase in NEU1 activity, following administration of all therapeutic agents in most of the fibroblasts tested. Interestingly, dietary supplementation of betaine, a natural amino acid derivative, in mouse models with residual NEU1 activity mimicking type I sialidosis, increased the levels of mutant NEU1 and resolved the oligosacchariduria. Overall these findings suggest that carefully balanced, unconventional dietary compounds in combination with conventional therapeutic approaches may prove to be beneficial for the treatment of sialidosis type I.

Highlights

Neuraminidase 1 (NEU1) is a lysosomal sialidase that initiates the hydrolysis of glycoproteins and oligo- or polysaccharides by removing terminal sialic acid residues from the non-reducing end of their glycan chains
In contrast to β-GAL that partially retains its activity outside the complex, NEU1 strictly depends on its association with protective protein/cathepsin A (PPCA) for proper folding, catalytic activation and stability in lysosomes [1,2]
The primary fibroblasts used in this study were derived from 12 patients with confirmed diagnosis of sialidosis type I

Summary

Introduction

Neuraminidase 1 (NEU1) is a lysosomal sialidase that initiates the hydrolysis of glycoproteins and oligo- or polysaccharides by removing terminal sialic acid residues from the non-reducing end of their glycan chains. NEU1 forms a high molecular weight complex with two other lysosomal enzymes, the acidic β-galactosidase (β-GAL) and the serine carboxypeptidase, protective protein/cathepsin A (PPCA) [1]. In contrast to β-GAL that partially retains its activity outside the complex, NEU1 strictly depends on its association with PPCA for proper folding, catalytic activation and stability in lysosomes [1,2]. In absence of a functional PPCA, NEU1 activity is no longer measurable and the enzyme is rapidly degraded. Loss of NEU1 enzymatic activity affects the lysosomal processing/degradation of several sialo-glycoconjugates, and results in the gradual accumulation of sialylated metabolites in tissues and in urinary excretion of sialyloligosaccharides, diagnostic hallmarks of both diseases

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