title: Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease.
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.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Spampanato
authors.forename: Erin
authors.initials: E
authors.lastname: Feeney
authors.forename: Lishu
authors.initials: L
authors.lastname: Li
authors.forename: Monica
authors.initials: M
authors.lastname: Cardone
authors.forename: Jeong-A
authors.initials: JA
authors.lastname: Lim
authors.forename: Fabio
authors.initials: F
authors.lastname: Annunziata
authors.forename: Hossein
authors.initials: H
authors.lastname: Zare
authors.forename: Roman
authors.initials: R
authors.lastname: Polishchuk
authors.forename: Rosa
authors.initials: R
authors.lastname: Puertollano
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005089:Exocytosis; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D000520:alpha-Glucosidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C484068:Tcfeb protein, mouse; D006003:Glycogen; D000520:alpha-Glucosidases