Neuronopathic Gaucher disease: Beyond lysosomal dysfunction.
Neuronopathic Gaucher disease: Beyond lysosomal dysfunction.
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DOI：
10.3389/fnmol.2022.934820
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发表时间：
2022
影响因子：
4.8
通讯作者：
Zanlungo, Silvana
中科院分区：
文献类型：
--
作者：
Arevalo, Nohela B.;Lamaizon, Cristian M.;Cavieres, Viviana A.;Burgos, Patricia V.;alvarez, Alejandra R.;Yanez, Maria J.;Zanlungo, Silvana
关键词：
戈谢病（GD）是一种遗传性疾病，由编码溶酶体酶β-葡萄糖脑苷脂酶（β-GC）的GBA 1基因的隐性突变引起。β-GC在溶酶体中将葡萄糖神经酰胺（GluCer）水解为葡萄糖和神经酰胺，其活性丧失导致GluCer在不同组织中蓄积。在严重的情况下，酶缺乏会引发炎症、器官肿大、骨病和神经变性。神经元病性戈谢病（nGD）包括两种不同形式的疾病，其特征在于对中枢神经系统（CNS）的慢性或急性损伤。由于溶酶体是GD中受影响的关键细胞器，因此揭示nGD病理机制的细胞和分子研究主要集中在溶酶体功能障碍上。然而，新的研究表明，其他细胞器的改变有助于nGD病理学。例如，由于β-GC活性丧失导致GluCer在溶酶体中的异常积累，导致钙从内质网（ER）释放过多，激活ER相关降解途径和未折叠蛋白反应。最近的证据表明，nGD中线粒体自噬发生改变，导致功能障碍的线粒体积累，这是疾病进展的关键因素。此外，nGD患者存在线粒体形态、膜电位、ATP产生和活性氧（ROS）水平增加的改变。关于分泌途径的其他细胞器（如高尔基体和外泌体）的潜在功能障碍知之甚少。本文综述了nGD中溶酶体以外的细胞器功能障碍的证据。我们简要介绍了细胞和动物模型和信号通路相关的揭示GD的病理机制和新的治疗靶点。
Gaucher disease (GD) is an inherited disorder caused by recessive mutations in the GBA1 gene that encodes the lysosomal enzyme β-glucocerebrosidase (β-GC). β-GC hydrolyzes glucosylceramide (GluCer) into glucose and ceramide in the lysosome, and the loss of its activity leads to GluCer accumulation in different tissues. In severe cases, enzymatic deficiency triggers inflammation, organomegaly, bone disease, and neurodegeneration. Neuronopathic Gaucher disease (nGD) encompasses two different forms of the disease, characterized by chronic or acute damage to the central nervous system (CNS). The cellular and molecular studies that uncover the pathological mechanisms of nGD mainly focus on lysosomal dysfunction since the lysosome is the key organelle affected in GD. However, new studies show alterations in other organelles that contribute to nGD pathology. For instance, abnormal accumulation of GluCer in lysosomes due to the loss of β-GC activity leads to excessive calcium release from the endoplasmic reticulum (ER), activating the ER-associated degradation pathway and the unfolded protein response. Recent evidence indicates mitophagy is altered in nGD, resulting in the accumulation of dysfunctional mitochondria, a critical factor in disease progression. Additionally, nGD patients present alterations in mitochondrial morphology, membrane potential, ATP production, and increased reactive oxygen species (ROS) levels. Little is known about potential dysfunction in other organelles of the secretory pathway, such as the Golgi apparatus and exosomes. This review focuses on collecting evidence regarding organelle dysfunction beyond lysosomes in nGD. We briefly describe cellular and animal models and signaling pathways relevant to uncovering the pathological mechanisms and new therapeutic targets in GD.
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影响因子：
7.8
作者：
Aflaki E;Moaven N;Borger DK;Lopez G;Westbroek W;Chae JJ;Marugan J;Patnaik S;Maniwang E;Gonzalez AN;Sidransky E
通讯作者：
Sidransky E
影响因子：
3.5
作者：
Awad, Ola;Sarkar, Chinmoy;Feldman, Ricardo A.
通讯作者：
Feldman, Ricardo A.
在GBA-N370S帕金森氏菌IPSC衍生的多巴胺神经元中，ER应力和自噬扰动导致细胞外α-突触核蛋白升高。
影响因子：
5.9
作者：
Fernandes HJ;Hartfield EM;Christian HC;Emmanoulidou E;Zheng Y;Booth H;Bogetofte H;Lang C;Ryan BJ;Sardi SP;Badger J;Vowles J;Evetts S;Tofaris GK;Vekrellis K;Talbot K;Hu MT;James W;Cowley SA;Wade-Martins R
通讯作者：
Wade-Martins R
影响因子：
16.2
作者：
Aflaki E;Westbroek W;Sidransky E
通讯作者：
Sidransky E
影响因子：
4.3
作者：
Brown, Robert A.;Voit, Antanina;Awad, Ola
通讯作者：
Awad, Ola