Drosophila melanogaster models of MPS IIIC (Hgsnat-deficiency) highlight the role of glia in disease presentation

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Laura Hewson, Amanda Choo, Dani L. Webber, Paul J. Trim, Marten F. Snel, Anthony O. Fedele, John J. Hopwood, Kim M. Hemsley, Louise V. O'Keefe
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引用次数: 0

Abstract

Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan-α-glucosaminide N-acetyltransferase (HGSNAT; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep–wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As HGSNAT is conserved in Drosophila melanogaster, we now describe the creation and characterisation of the first Drosophila models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi-mediated knockdown of hgsnat were confirmed to have a reduced level of HGSNAT transcripts and age-dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre-synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in hgsnat neuronal knockdown lines. Further, when hgsnat was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that hgsnat function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.

Abstract Image

黑腹果蝇的 MPS IIIC(Hgsnat 缺乏症)模型突显了神经胶质细胞在疾病表现中的作用。
桑菲利波综合征(粘多糖病 III 型或 MPS III)是一种隐性遗传的神经退行性溶酶体贮积症。编码硫酸肝素降解途径中酶的基因发生突变,导致部分降解的硫酸肝素蓄积,最终导致神经系统缺陷。编码膜蛋白肝素-α-氨基葡萄糖 N-乙酰转移酶(HGSNAT;EC2.3.1.78)的基因发生突变会导致 MPS IIIC(OMIM#252930),表现为认知功能受损、睡眠-觉醒周期改变、多动和早死,通常在成年前死亡。导致症状出现的确切疾病机制仍不清楚,这对开发有效疗法构成了巨大挑战。由于 HGSNAT 在黑腹果蝇中是保守的,我们现在描述第一个 MPS IIIC 果蝇模型的创建和特征。经证实,具有内源性插入突变或 RNAi- 介导的 hgsnat 基因敲除的果蝇,其 HGSNAT 转录物水平降低,硫酸肝素随年龄的增长而积累,导致内/溶酶体区室的堵塞。这导致前突触异常、爬行缺陷和整体活动减少。在敲除 hgsnat 的神经元系中,可以看到昼夜节律的改变(早晨活动高峰的转移)。此外,当敲除特定神经胶质亚群(包裹、皮质、星形胶质细胞或脑膜下神经胶质细胞)中的 hgsnat 时,会发现爬行受损或活动减少,这意味着这些特定神经胶质亚群中的 hgsnat 功能在很大程度上导致了这种行为,而针对这些细胞群的治疗可能是改善或预防症状发作所必需的。这些新型 MPS IIIC 模型提供了重要的研究工具,有助于确定导致这种目前尚无法治疗的疾病发生神经变性的关键细胞通路。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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