Neuromuscular degeneration and locomotor deficit in a Drosophila model of mucopolysaccharidosis VII is attenuated by treatment with resveratrol.

Sudipta Bar,Rupak Datta,Mohit Prasad

doi:10.1242/dmm.036954

Sudipta Bar, Rupak Datta + Show 1 more

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https://doi.org/10.1242/dmm.036954

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Abstract

ABSTRACTMucopolysaccharidosis VII (MPS VII) is a recessively inherited lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. The disease is characterized by widespread accumulation of non-degraded or partially degraded glycosaminoglycans, leading to cellular and multiple tissue dysfunctions. The patients exhibit diverse clinical symptoms, and eventually succumb to premature death. The only possible remedy is the recently approved enzyme replacement therapy, which is an expensive, invasive and lifelong treatment procedure. Small-molecule therapeutics for MPS VII have so far remained elusive primarily due to lack of molecular insights into the disease pathogenesis and unavailability of a suitable animal model that can be used for rapid drug screening. To address these issues, we developed a Drosophila model of MPS VII by knocking out the CG2135 gene, the fly β-glucuronidase orthologue. The CG2135−/− fly recapitulated cardinal features of MPS VII, such as reduced lifespan, progressive motor impairment and neuropathological abnormalities. Loss of dopaminergic neurons and muscle degeneration due to extensive apoptosis was implicated as the basis of locomotor deficit in this fly. Such hitherto unknown mechanistic links have considerably advanced our understanding of the MPS VII pathophysiology and warrant leveraging this genetically tractable model for deeper enquiry about the disease progression. We were also prompted to test whether phenotypic abnormalities in the CG2135−/− fly can be attenuated by resveratrol, a natural polyphenol with potential health benefits. Indeed, resveratrol treatment significantly ameliorated neuromuscular pathology and restored normal motor function in the CG2135−/− fly. This intriguing finding merits further preclinical studies for developing an alternative therapy for MPS VII.This article has an associated First Person interview with the first author of the paper.

Highlights

Mucopolysaccharidosis VII (MPS VII), known as Sly syndrome, is a recessively inherited lysosomal storage disorder caused by β-glucuronidase (β-GUS) deficiency
Widespread expression of CG2135 mRNA was confirmed by reverse transcription (RT)-PCR, which is consistent with a previous microarray-based transcriptome analysis (Fig. S2) (Chintapalli et al, 2007)
The locomotor deficit in the CG2135−/− fly was quite striking. This could be attributed to neuromuscular degeneration, the loss of dopaminergic neurons and muscle cell apoptosis

Summary

Introduction

Mucopolysaccharidosis VII (MPS VII), known as Sly syndrome, is a recessively inherited lysosomal storage disorder caused by β-glucuronidase (β-GUS) deficiency. Because of heterogeneity of mutations in the β-GUS gene (GUSB) that results in varying extents of enzyme deficiency, MPS VII patients exhibit diverse clinical symptoms, leading to premature death in most cases. Cognitive disability, skeletal abnormality, motor impairment, hernias, hepatosplenomegaly, hydrops fetalis, and heart and respiratory problems are some of the common clinical signs seen in MPS VII. Many of these symptoms are manifested in other MPS disorders, suggesting a common pathophysiological mechanism for this group of disorders (Montaño et al, 2016; Neufeld and Muenzer, 2014; Sly et al, 1973; Zielonka et al, 2017). A clinical trial for enzyme replacement therapy with recombinant human β-GUS led to FDA approval of the drug in November, 2017 (Fox et al, 2015; Harmatz et al, 2018)

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