Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: implications for therapy.
Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: implications for therapy.
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DOI：
10.1016/j.ymgme.2010.08.001
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发表时间：
2010-12
影响因子：
3.8
通讯作者：
Plotz, Paul H.
中科院分区：
文献类型：
--
作者：
Raben, Nina;Ralston, Evelyn;Chien, Yin-Hsiu;Baum, Rebecca;Schreiner, Cynthia;Hwu, Wuh-Liang;Zaal, Kristien J. M.;Plotz, Paul H.
Pompe病是一种由于酸性α-葡萄糖苷酶缺乏而引起的溶酶体储存障碍，酸性α-葡萄糖苷酶是一种降解溶酶体中糖原的酶。这种疾病在婴儿中表现为一种致命的心肌病和骨骼肌病；在较轻的晚发性形式中，骨骼肌是主要的受累组织。我们先前已经证明，在成年患者和小鼠模型中，肌肉中的自噬内含物是显著的。在这项研究中，我们评估了婴儿自噬病理在酶替代治疗前和治疗后6个月的贡献。从肌肉活检中分离出的单个肌肉纤维，进行自噬和溶酶体标记染色，并在共聚焦显微镜下进行分析。此外，对未染色的固定肌束进行二次谐波成像分析。出乎意料的是，在青少年和成人患者中如此突出的自噬成分在婴儿中可以忽略不计；相反，压倒性的特征是存在巨大扩张的溶酶体。然而，在治疗6个月后，自噬的积聚变得明显，就像被糖原清除所掩盖一样。在大多数纤维中，这两种病理似乎并不共存。这些数据表明，在婴儿和成人中，庞贝病的发病机制可能存在差异。
Pompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase, the enzyme that degrades glycogen in the lysosomes. The disease manifests as a fatal cardiomyopathy and skeletal muscle myopathy in infants; in milder late-onset forms skeletal muscle is the major tissue affected. We have previously demonstrated that autophagic inclusions in muscle are prominent in adult patients and the mouse model. In this study we have evaluated the contribution of the autophagic pathology in infants before and 6 months after enzyme replacement therapy. Single muscle fibers, isolated from muscle biopsies, were stained for autophagosomal and lysosomal markers and analyzed by confocal microscopy. In addition, unstained bundles of fixed muscles were analyzed by second harmonic imaging. Unexpectedly, the autophagic component which is so prominent in juvenile and adult patients was negligible in infants; instead, the overwhelming characteristic was the presence of hugely expanded lysosomes. After 6 months on therapy, however, the autophagic buildup becomes visible as if unmasked by the clearance of glycogen. In most fibers, the two pathologies did not seem to coexist. These data point to the possibility of differences in the pathogenesis of Pompe disease in infants and adults.
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