Pompe disease: from pathophysiology to therapy and back again.
Pompe disease: from pathophysiology to therapy and back again.
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DOI：
10.3389/fnagi.2014.00177
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发表时间：
2014
影响因子：
4.8
通讯作者：
Raben N
中科院分区：
文献类型：
--
作者：
Lim JA;Li L;Raben N
庞贝氏症是一种溶酶体贮积症，其中酸性α-葡糖苷酶（GAA）缺乏或不存在。这种溶酶体酶的缺乏导致多种组织中充满糖原的溶酶体的进行性扩张，其中心肌和骨骼肌受到最严重的影响。临床范围从婴儿的致死性肥厚型心肌病和骨骼肌肌病到相对减弱的形式，表现为进行性肌病而不涉及心脏。目前可用的酶替代疗法（ERT）被证明是成功的逆转心脏，但不是骨骼肌异常。虽然对这种疾病的总体认识已经取得了进展，但肌肉损伤的病理生理学仍然知之甚少。溶酶体增大/破裂长期以来被认为是庞贝氏症中无情肌肉损伤的机制。在过去的几年中，很明显，这种简单的病理学观点是不够的;病理级联涉及功能失调的自噬，一种主要的溶酶体依赖性细胞内降解途径。庞贝氏症骨骼肌中的自噬过程在终末阶段受损的自噬小体-溶酶体融合中受到影响。患病肌肉的另一个异常是加速产生与衰老无关的大量脂褐素沉积物这是细胞氧化损伤的标志，也是线粒体功能障碍的标志。大量的自噬积聚和脂褐质内含物似乎比自噬区域外的扩大的溶酶体对肌肉结构产生更大的影响。此外，功能失调的自噬影响替代酶的运输并干扰其递送至溶酶体。已经在庞贝氏症小鼠模型中测试了几种新的治疗方法：底物减少疗法，转录因子EB和密切相关但不同的因子E3过表达后的溶酶体胞吐，以及自噬的遗传操纵。
Pompe disease is a lysosomal storage disorder in which acid alpha-glucosidase (GAA) is deficient or absent. Deficiency of this lysosomal enzyme results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected. The clinical spectrum ranges from fatal hypertrophic cardiomyopathy and skeletal muscle myopathy in infants to relatively attenuated forms, which manifest as a progressive myopathy without cardiac involvement. The currently available enzyme replacement therapy (ERT) proved to be successful in reversing cardiac but not skeletal muscle abnormalities. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal enlargement/rupture has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, it became clear that this simple view of the pathology is inadequate; the pathological cascade involves dysfunctional autophagy, a major lysosome-dependent intracellular degradative pathway. The autophagic process in Pompe skeletal muscle is affected at the termination stage—impaired autophagosomal-lysosomal fusion. Yet another abnormality in the diseased muscle is the accelerated production of large, unrelated to ageing, lipofuscin deposits—a marker of cellular oxidative damage and a sign of mitochondrial dysfunction. The massive autophagic buildup and lipofuscin inclusions appear to cause a greater effect on muscle architecture than the enlarged lysosomes outside the autophagic regions. Furthermore, the dysfunctional autophagy affects the trafficking of the replacement enzyme and interferes with its delivery to the lysosomes. Several new therapeutic approaches have been tested in Pompe mouse models: substrate reduction therapy, lysosomal exocytosis following the overexpression of transcription factor EB and a closely related but distinct factor E3, and genetic manipulation of autophagy.
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影响因子：
64.5
作者：
Demetriades C;Doumpas N;Teleman AA
通讯作者：
Teleman AA
影响因子：
3.5
作者：
Bijvoet, AGA;van de Kamp, EHM;van der Ploeg, AT
通讯作者：
van der Ploeg, AT
DOI：
10.1007/bf02248461
发表时间：
1932-01-01
期刊：
Zeitschrift fur Kinderheilkunde
影响因子：
--
作者：
Bischoff, G.
通讯作者：
Bischoff, G.
影响因子：
14.5
作者：
ENGEL, AG
通讯作者：
ENGEL, AG
影响因子：
19
作者：
Bar-Peled, Liron;Sabatini, David M.
通讯作者：
Sabatini, David M.