Abstract
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that occurs due to the deficit of the lysosomal enzyme iduronate 2-sulfatase (IDS) that leads to the storage of the glycosaminoglycan heparan- and dermatan-sulfate in all organs and tissues. It is characterized by important clinical features and the severe form presents with a heavy neurological involvement. However, almost nothing is known about the neuropathogenesis of MPS II. To address this issue, we developed a ubiquitous, neuronal, and glial-specific knockdown model in Drosophila melanogaster by using the RNA interference (RNAi) approach. Knockdown of the Ids/CG12014 gene resulted in a significant reduction of the Ids gene expression and enzymatic activity. However, glycosaminoglycan storage, survival, molecular markers (Atg8a, Lamp1, Rab11), and locomotion behavior were not affected. Even strongly reduced, IDS-activity was enough to prevent a pathological phenotype in a MPS II RNAi fruit fly. Thus, a Drosophila MPS II model requires complete abolishment of the enzymatic activity.
Highlights
We developed a ubiquitous, neuronal, and glial-specific knockdown model in Drosophila melanogaster by using the RNA interference (RNAi) approach
iduronate 2-sulfatase (IDS)-activity was enough to prevent a pathological phenotype in a Mucopolysaccharidosis type II (MPS II) RNAi fruit fly
Mucopolysaccharidosis type II (MPS II, or Hunter Syndrome, MIM #309900) is a rare X-linked lysosomal storage disorder caused by the deficit of the iduronate 2-sulfatase (IDS, EC3.1.6.13) enzyme, leading to storage of the glycosaminoglycans (GAGs), heparan- and dermatan-sulfate in all organs and tissues
Summary
Mucopolysaccharidosis type II (MPS II, or Hunter Syndrome, MIM #309900) is a rare X-linked lysosomal storage disorder caused by the deficit of the iduronate 2-sulfatase (IDS, EC3.1.6.13) enzyme, leading to storage of the glycosaminoglycans (GAGs), heparan- and dermatan-sulfate in all organs and tissues. MPS II has an incidence rate of 0.38–1.09 per 100,000 live newborns [1]. It is characterized by progressive important clinical features, including organomegaly, cardiopathies, joint stiffness, multiple dysostoses, and skeletal deformities [2]. Patients are usually classified in attenuated or severe based on the absence or presence of the neurological involvement. The attenuated form presents normal intelligence and extended life expectancy. Patients with severe phenotype are characterized by a heavy neurological involvement already present in infancy, with impaired cognitive abilities, delayed mental development, and behavioral problems. No differences in the IDS enzymatic activity were observed between the attenuated and severe form, and all MPS II patients present no residual IDS activity [2]
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