Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
EMBO Mol Med. 2013 May;5(5):691-706. doi: 10.1002/emmm.201202176. Epub 2013 Apr 18.
A recently proposed therapeutic approach for lysosomal storage disorders (LSDs) relies upon the ability of transcription factor EB (TFEB) to stimulate autophagy and induce lysosomal exocytosis leading to cellular clearance. This approach is particularly attractive in glycogen storage disease type II [a severe metabolic myopathy, Pompe disease (PD)] as the currently available therapy, replacement of the missing enzyme acid alpha-glucosidase, fails to reverse skeletal muscle pathology. PD, a paradigm for LSDs, is characterized by both lysosomal abnormality and dysfunctional autophagy. Here, we show that TFEB is a viable therapeutic target in PD: overexpression of TFEB in a new muscle cell culture system and in mouse models of the disease reduced glycogen load and lysosomal size, improved autophagosome processing, and alleviated excessive accumulation of autophagic vacuoles. Unexpectedly, the exocytosed vesicles were labelled with lysosomal and autophagosomal membrane markers, suggesting that TFEB induces exocytosis of autophagolysosomes. Furthermore, the effects of TFEB were almost abrogated in the setting of genetically suppressed autophagy, supporting the role of autophagy in TFEB-mediated cellular clearance.
最近提出的一种治疗溶酶体贮积症（LSD）的方法依赖于转录因子 EB（TFEB）刺激自噬并诱导溶酶体胞吐的能力，从而导致细胞清除。这种方法在糖原贮积病 II 型（一种严重的代谢性肌病，庞贝病（PD））中特别有吸引力，因为目前可用的治疗方法，即缺失酶酸性α-葡萄糖苷酶的替代疗法，无法逆转骨骼肌病理学。PD 是 LSD 的典范，其特征是溶酶体异常和功能失调的自噬。在这里，我们表明 TFEB 是 PD 中的一个可行的治疗靶点：在新的肌细胞培养系统和疾病小鼠模型中过表达 TFEB 可减少糖原负荷和溶酶体大小，改善自噬体处理，并减轻过度积累的自噬空泡。出乎意料的是，胞吐的囊泡被溶酶体和自噬体膜标记物标记，表明 TFEB 诱导了自噬溶酶体的胞吐。此外，在遗传抑制自噬的情况下，TFEB 的作用几乎被消除，这支持了自噬在 TFEB 介导的细胞清除中的作用。
