Autophagosome maturation is impaired in Fabry disease
Autophagosome maturation is impaired in Fabry disease
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DOI：
10.4161/auto.6.5.11943
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发表时间：
2010-07-01
期刊：
影响因子：
13.3
通讯作者：
Bekri, Soumeya
中科院分区：
文献类型：
--
作者：
Chevrier, Marc;Brakch, Noureddine;Bekri, Soumeya
法布里病是一种由α-半乳糖苷酶A缺乏引起的溶酶体贮积症（LSD）。该病的特点是严重的主要器官受累，但病理机制尚未阐明。据报道，其他LSD的自噬过程中断，但尚未在法布里病中进行研究。肾活检获得5名成年男性法布里病患者之前和之后的三年的酶替代疗法（ERT）与半乳糖苷酶α。与对照组相比，所有患者的肾活检中均观察到胆固醇蓄积。ERT治疗3年后，主要在肾内皮细胞和系膜细胞中观察到空泡数量减少。在来自法布里病患者的培养细胞中测量LC 3（一种特异性自噬标志物）的水平显示，与来自非法布里病受试者的细胞相比，基础水平增加，并且与非法布里病细胞相比，响应饥饿的增加更大。在蛋白酶抑制剂存在下的饥饿并没有导致法布里病细胞中LC 3的显著增加，而在非法布里病细胞中观察到LC 3的进一步增加，这一观察结果与法布里病中受损的自噬通量一致。与对照细胞相比，法布里成纤维细胞中LC 3 mRNA的过表达与自噬的上调一致。此外，肾组织和培养的法布里病患者成纤维细胞中的LC 3和p62/SQSTM 1（与LC 3结合）染色支持自噬通量受损。这些发现表明法布里病与自噬失调有关。
Fabry disease is a lysosomal storage disorder (LSD) caused by a deficiency in alpha-galactosidase A. The disease is characterized by severe major organ involvement, but the pathologic mechanisms responsible have not been elucidated. Disruptions of autophagic processes have been reported for other LSDs, but have not yet been investigated in Fabry disease. Renal biopsies were obtained from five adult male Fabry disease patients before and after three years of enzyme replacement therapy (ERT) with agalsidase alfa. Vacuole accumulation was seen in renal biopsies from all patients compared with control biopsies. Decreases in the number of vacuoles were seen after three years of ERT primarily in renal endothelial cells and mesangial cells. Measurement of the levels of LC3, a specific autophagy marker, in cultured cells from Fabry patients revealed increased basal levels compared to cells from non-Fabry subjects and a larger increase in response to starvation than seen in non-Fabry cells. Starvation in the presence of protease inhibitors did not result in a significant increase in LC3 in Fabry cells, whereas a further increase in LC3 was observed in non-Fabry cells, an observation that is consistent with impaired autophagic flux in Fabry disease. Overexpression of LC3 mRNA in Fabry fibroblasts compared to control cells is consistent with an upregulation of autophagy. Furthermore, LC3 and p62/SQSTM1 (that binds to LC3) staining in renal tissues and in cultured fibroblasts from Fabry patients supports impairment of autophagic flux. These findings suggest that Fabry disease is linked to a deregulation of autophagy.