中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2017, Vol. 12 ›› Issue (3): 380-384.doi: 10.4103/1673-5374.202934

• 综述:退行性病与再生 • 上一篇    下一篇

自噬溶酶体功能障碍在戈谢病和帕金森病中的新兴作用

  

  • 收稿日期:2017-03-06 出版日期:2017-03-15 发布日期:2017-03-15

The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson’s disease

Kerri J. Kinghorn1, 2, 3, Amir M. Asghari4, Jorge Iván Castillo-Quan1, 5, 6   

  1. 1 Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London, UK; 2 Institute of Neurology, University College London, London, UK; 3 Department of Basic and Clinical Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, London, UK; 4 London Central & West Unscheduled Care Collaborative, St. Charles Centre for Health and Wellbeing, Exmoor Street St, Charles Hospital, London, UK; 5 Research Division, Joslin Diabetes Center, Boston, MA, USA; 6 Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA
  • Received:2017-03-06 Online:2017-03-15 Published:2017-03-15
  • Contact: Kerri J. Kinghorn, M.D., Ph.D.,k.kinghorn@ucl.ac.uk.

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摘要：

戈谢病（GD）是最常见的溶酶体储存障碍，其原因是葡萄糖脑苷脂酶（GCase）缺乏或继发于GBA1基因突变的功能缺陷。而GBA1突变与帕金森病（PD）之间存在明确关联，实际上GBA1突变现在被认为是PD的最大遗传风险因子。细胞蛋白质受损溶酶体包括α-突触核蛋白，是一种涉及PD发病机制的自噬降解，而这一结论在GD和GBA1-PD中也得到了越来越多的证据。本文在缺乏神经元GCase的果蝇模型中显示出与突触损失和神经变性相关的清晰溶酶体 - 自噬缺陷。此外，还有一些其他的最新研究已经显示了自噬溶酶体系（ALS）功能障碍，伴随伴侣介导的自噬（CMA）以及GDau和GBA1-PD模型系统中的巨噬样蛋白特异性缺陷。最后，文章讨论了使用药物如雷帕霉素抑制mTOR以逆转GD和PD中的自噬缺陷的可能治疗获益。

ORCID:0000-0003-2048-4332(Kerri J. Kinghorn);0000-0002-6324-2854(Jorge Iván Castillo-Quan)

Abstract:

Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in the GBA1 gene. There is an established association between GBA1 mutations and Parkinson’s disease (PD), and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD. Impaired lysosomal-autophagic degradation of cellular proteins, including α-synuclein (α-syn), is implicated in the pathogenesis of PD, and there is increasing evidence for this also in GD and GBA1-PD. Indeed we have recently shown in a Drosophila model lacking neuronal GCase, that there are clear lysosomal-autophagic defects in association with synaptic loss and neurodegeneration. In addition, we demonstrated alterations in mechanistic target of rapamycin complex 1 (mTORC1) signaling and functional rescue of the lifespan, locomotor defects and hypersensitivity to oxidative stress on treatment of GCase-deficient flies with the mTOR inhibitor rapamycin. Moreover, a number of other recent studies have shown autophagy-lysosomal system (ALS) dysfunction, with specific defects in both chaperone-mediated autophagy (CMA), as well as macroautophagy, in GD and GBA1-PD model systems. Lastly we discuss the possible therapeutic benefits of inhibiting mTOR using drugs such as rapamycin to reverse the autophagy defects in GD and PD.

Key words: Gaucher disease, Parkinson’s disease, Drosophila, autophagy, lysosome, glucocerebrosidase, GBA