Transcription factor EB TFEB is a new therapeuti

Authors: Carmine Spampanato Erin Feeney Lishu Li Monica Cardone Jeong‐A Lim Fabio Annunziata Hossein Zare Roman Polishchuk Rosa Puertollano Giancarlo Parenti Andrea Ballabio Nina Raben

Publish Date: 2013/05/07

Volume: 5, Issue: 5, Pages: 691-706

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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 clearanceThe major problem with the current ERT for several LSDs is inefficient drug delivery to lysosomes in particular target tissues Furthermore the therapy does not address autophagic abnormalities which are commonly found in LSDs These limitations are apparent in PD a severe metabolic myopathy due to a deficiency of glycogen‐degrading lysosomal enzyme GAA Experimental data and clinical experience over the past decade provide strong evidence of skeletal muscle resistance to therapy with recombinant human GAA Here we have tested a recently developed approach for therapy of LSDs in PD mouse models This new approach circumvents the problem of ineffective drug delivery and involves manipulation of TFEBFor testing the novel therapeutic approach we developed new PD models Experiments in PD cell culture and animal models demonstrate that TFEB has the capacity to rid muscle cells of excessive glycogen burden and accumulation of autophagic debris Overexpression of TFEB in muscle cells or in Pompe mice stimulated fusion between lysosomes and autophagosomes resulting in an increased formation and exocytosis of autolysosomes Unexpectedly the effects of TFEB were almost abolished when autophagy was genetically suppressed

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