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首页> 外文学位 >Unraveling the causative defects in X-linked myopathy with excessive autophagy.
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Unraveling the causative defects in X-linked myopathy with excessive autophagy.

机译：揭示过度自噬导致X连锁肌病的病因缺陷。

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摘要

X-linked myopathy with excessive autophagy (XMEA) is a skeletal muscle disorder inherited in recessive fashion, affecting boys and sparing carrier females. Onset is in childhood with weakness of the proximal muscles of the lower extremities, progressing slowly to involve other muscle groups. Pathological analysis of skeletal muscle biopsies shows no inflammation, necrosis or apoptosis. Instead, forty to 80% of fibers exhibit giant autophagic vacuoles with heterogeneous degradative content.;The aim of my project was a better understanding of XMEA pathogenesis, with a focus on finding the disease-causing gene.;In this thesis, I identify mutations in XMEA patients in a novel, previously uncharacterized gene, which we name VMA21. Most of the mutations are located in splicing-relevant positions and decrease splicing efficiency. After establishing that XMEA is caused by hypomorphic alleles of the VMA21 gene, I show that VMA21 is the diverged human orthologue of the yeast Vma21p protein, and that like Vma21p, it is an essential assembly chaperone of the V-ATPase. Decreased VMA21 reduces V-ATPase activity, resulting in altered lysosomal pH and a blockage at the degradative step of autophagy. Towards understanding disease pathogenesis, I show evidence of compensatory autophagy upregulation consecutive to the impaired clearance. Accumulated autolysosomes due to increased autophagy continue to face the degradative block and are slow to disappear. Instead, they merge to each other and form the characteristic giant XMEA vacuoles. These results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.;This work describes the clinical outcome at the cusp of tolerable reduction in V-ATPase, with implications on common diseases like osteoporosis and cancer metastasis, where increased V-ATPase activity is an important component. Our XMEA patients show that the safety margin of reducing V-ATPase activity in humans is wide, increasing the potential to utilize chemical or biological V-ATPase inhibitors as possible therapies.;Numerous critical functions of all cells are compartmentalized in particular pH environments established by the intracellular transmembrane V-ATPase proton pump complex. Assembly of this complex, directed by the Vma21p chaperone, is well-studied in yeast but completely unknown in other organisms.
机译：X连锁性肌病伴自噬过多（XMEA）是一种以隐性方式遗传的骨骼肌疾病，影响男孩和女性母犬。发病于儿童期，下肢近端肌肉无力，进展缓慢，涉及其他肌肉群。骨骼肌活检的病理分析未显示炎症，坏死或凋亡。取而代之的是，有40％至80％的纤维表现出具有异质降解含量的巨大自噬泡。;我的项目目的是更好地了解XMEA发病机理，重点是寻找致病基因。在XMEA患者中发现了一个以前未知的新基因，我们将其命名为VMA21。大多数突变位于与剪接相关的位置，降低了剪接效率。在确定XMEA由VMA21基因的亚同等位基因引起后，我证明VMA21是酵母Vma21p蛋白的人类直向同源物，并且与Vma21p一样，它是V-ATPase的必需装配伴侣。 VMA21降低会降低V-ATPase活性，从而导致溶酶体pH值改变和自噬降解步骤的阻断。为了了解疾病的发病机理，我证明了自清除率起连续发生代偿性自噬上调的证据。由于自噬增加导致积累的自溶酶体继续面对降解障碍，并缓慢消失。相反，它们彼此融合形成了特征性的XMEA液泡。这些结果揭示了一种新的疾病机制，即导致细胞空泡化和组织萎缩的巨噬细胞自噬过度补偿。这项工作描述了可耐受V-ATPase降低的临床结果，并涉及骨质疏松和癌症转移等常见疾病，其中V-ATPase活性增加是重要组成部分。我们的XMEA患者表明，降低人类V-ATPase活性的安全性范围很广，增加了使用化学或生物V-ATPase抑制剂作为可能疗法的可能性。;在特定的pH环境下，所有细胞的许多关键功能都被分隔开细胞内跨膜V-ATPase质子泵复合物。由Vma21p分子伴侣控制的这种复合物的组装在酵母中已得到充分研究，而在其他生物中则完全未知。

著录项

  • 作者

    Oprea, Iulia.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Biology Genetics.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 211 p.
  • 总页数 211
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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