A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin
A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin
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DOI：
10.1523/jneurosci.4527-15.2016
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发表时间：
2016-11-16
影响因子：
5.3
通讯作者：
Partridge, Linda
中科院分区：
文献类型：
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作者：
Kinghorn, Kerri J.;Groenke, Sebastian;Partridge, Linda
葡糖脑苷脂酶（GBA 1）突变与戈谢病（GD）相关，戈谢病是一种由葡糖脑苷脂酶（GBA）功能缺陷引起的常染色体隐性遗传病，GBA是一种将葡糖神经酰胺水解为神经酰胺和葡萄糖的溶酶体酶。GD的神经病理形式可与快速神经功能衰退（II型）相关，或表现为具有广泛神经体征的慢性形式（III型）。此外，GBA 1突变和帕金森病（PD）之间存在着明确的联系，GBA 1中的杂合子突变被认为是PD中最常见的遗传缺陷。在这里，我们描述了一种新的果蝇GD模型，缺乏两个苍蝇GBA 1直系同源。该敲除模型概括了GD在细胞水平上的主要特征，具有严重的溶酶体缺陷和蝇脑中葡糖神经酰胺的积累。我们还证明了自噬通量的阻断与dGBA缺陷的苍蝇大脑中的寿命缩短、年龄依赖性运动缺陷和自噬底物积累相关。此外，雷帕霉素（mTOR）信号传导的机制靶标在dGBA敲除的果蝇中下调，伴随着Mitf基因表达（哺乳动物TFEB的果蝇直系同源物）的上调，可能是对自噬阻断的补偿性反应。此外，mTOR抑制剂雷帕霉素能够部分改善寿命、运动和氧化应激表型。总之，我们的研究结果表明，这种dGBA 1缺陷的果蝇模型是一个有用的平台，进一步研究溶酶体自噬损伤的作用和雷帕霉素在神经元病性GD中的潜在治疗益处。这些结果也对自噬和mTOR信号在GBA 1相关PD中的作用具有重要意义。
Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD. Here we describe a novel Drosophila model of GD that lacks the two fly GBA1 orthologs. This knock-out model recapitulates the main features of GD at the cellular level with severe lysosomal defects and accumulation of glucosylceramide in the fly brain. We also demonstrate a block in autophagy flux in association with reduced lifespan, age-dependent locomotor deficits and accumulation of autophagy substrates in dGBA-deficient fly brains. Furthermore, mechanistic target of rapamycin (mTOR) signaling is downregulated in dGBA knock-out flies, with a concomitant upregulation of Mitf gene expression, the fly ortholog of mammalian TFEB, likely as a compensatory response to the autophagy block. Moreover, the mTOR inhibitor rapamycin is able to partially ameliorate the lifespan, locomotor, and oxidative stress phenotypes. Together, our results demonstrate that this dGBA1-deficient fly model is a useful platform for the further study of the role of lysosomal-autophagic impairment and the potential therapeutic benefits of rapamycin in neuronopathic GD. These results also have important implications for the role of autophagy and mTOR signaling in GBA1-associated PD.