Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur 741246, West Bengal, India.
Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur 741246, West Bengal, India
Dis Model Mech. 2018 Nov 20;11(11):dmm036954. doi: 10.1242/dmm.036954.
Mucopolysaccharidosis 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 model of MPS VII by knocking out the gene, the fly β-glucuronidase orthologue. The 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 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 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.
黏多糖贮积症 VII 型（MPS VII）是一种由β-葡糖醛酸酶缺乏引起的常染色体隐性遗传性溶酶体贮积症。该疾病的特征是广泛积累未降解或部分降解的糖胺聚糖，导致细胞和多种组织功能障碍。患者表现出不同的临床症状，最终导致过早死亡。唯一可能的治疗方法是最近批准的酶替代疗法，但该疗法昂贵、具有侵入性且需要终身治疗。MPS VII 的小分子治疗方法迄今仍难以实现，主要是因为缺乏对疾病发病机制的分子认识，并且缺乏可用于快速药物筛选的合适动物模型。为了解决这些问题，我们通过敲除 基因（果蝇β-葡糖醛酸酶的同源基因），建立了 MPS VII 的模型。该果蝇模型再现了 MPS VII 的主要特征，例如寿命缩短、进行性运动障碍和神经病理学异常。多巴胺能神经元丧失和肌肉退化导致广泛凋亡，这可能是该果蝇运动障碍的基础。这种以前未知的机制联系极大地促进了我们对 MPS VII 病理生理学的理解，并促使我们利用这种遗传上易于操作的模型，更深入地研究疾病的进展。我们还试图测试白藜芦醇（一种具有潜在健康益处的天然多酚）是否可以减轻 果蝇中的表型异常。事实上，白藜芦醇治疗显著改善了 果蝇的神经肌肉病理学，并恢复了其正常运动功能。这一有趣的发现值得进一步进行临床前研究，以开发 MPS VII 的替代疗法。本文附有该论文第一作者的第一人称采访。
