Abstract
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.
Highlights
Pompe disease (PD; OMIM 232300) is a severe metabolic myopathy caused by the deficiency of acid alpha-glucosidase (GAA; acid maltase, E.C.3.2.1.20), an enzyme responsible for (1) Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy (2) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA (3) Jan and Dan Duncan Neurological Research Institute, Texas Children ySpampanato and Feeney contributed as the two co-first authors. zLi, Cardone, Lim, and Annunziata contributed among themselves.breaking down glycogen to glucose within the acidic environment of lysosomes
Autophagic pathology was clearly visible in muscle fibres from a newly developed PD mouse model, in which autophagosomes are labelled with GFP-LC3 (GFPLC3:GAAÀ/À)
This build-up poses an obstacle for Enzyme replacement therapy (ERT): when labelled recombinant human GAA (rhGAA) was administered i.v. in these mice, the drug was detected almost exclusively within autophagosomes clustered in the build-up areas (Fig 2)
Summary
GAA deficiency is a systemic disorder – distended glycogenfilled lysosomes can be found in multiple tissues – but skeletal and cardiac muscles are vulnerable to the accumulation of storage material. In the attenuated phenotypes, characterized by later (childhood, juvenile or adult) onset, cardiac muscle is usually spared, but the illness remains a serious condition with progressive motor impairment, Published 2013. This is a US Government work and is in the public domain in the USA.
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