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PMID: 23630012 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease.

EMBO molecular medicine ·Vol. 5 ·No. 6 ·2013-06-00 ·Pages 870-90

Nemazanyy I, Blaauw B, Paolini C, Caillaud C, Protasi F, Mueller A, Proikas-Cezanne T, Russell RC, Guan KL, Nishino I, Sandri M, Pende M, Panasyuk G

Abstract

The complex of Vacuolar Protein Sorting 34 and 15 (Vps34 and Vps15) has Class III phosphatidylinositol 3-kinase activity and putative roles in nutrient sensing, mammalian Target Of Rapamycin (mTOR) activation by amino acids, cell growth, vesicular trafficking and autophagy. Contrary to expectations, here we show that Vps15-deficient mouse tissues are competent for LC3-positive autophagosome formation and maintain mTOR activation. However, an impaired lysosomal function in mutant cells is traced by accumulation of adaptor protein p62, LC3 and Lamp2 positive vesicles, which can be reverted to normal levels after ectopic overexpression of Vps15. Mice lacking Vps15 in skeletal muscles, develop a severe myopathy. Distinct from the autophagy deficient Atg7(-/-) mutants, pathognomonic morphological hallmarks of autophagic vacuolar myopathy (AVM) are observed in Vps15(-/-) mutants, including elevated creatine kinase plasma levels, accumulation of autophagosomes, glycogen and sarcolemmal features within the fibres. Importantly, Vps34/Vps15 overexpression in myoblasts of Danon AVM disease patients alleviates the glycogen accumulation. Thus, the activity of the Vps34/Vps15 complex is critical in disease conditions such as AVMs, and possibly a variety of other lysosomal storage diseases.

MeSH Terms
Animals Autophagy Autophagy-Related Protein 7 Cell Line Class III Phosphatidylinositol 3-Kinases/metabolism Humans Lysosomal Storage Diseases/metabolism,pathology Lysosomal-Associated Membrane Protein 2/metabolism Mice Mice, Knockout Microtubule-Associated Proteins/deficiency,genetics,metabolism Muscle, Skeletal/metabolism,physiopathology,ultrastructure Muscular Diseases/metabolism,pathology TOR Serine-Threonine Kinases/genetics,metabolism Transcription Factor TFIIH Transcription Factors/metabolism Vacuolar Sorting Protein VPS15/genetics,metabolism
Chemicals
Atg7 protein, mouse Gtf2h1 protein, mouse Lysosomal-Associated Membrane Protein 2 Map1lc3b protein, mouse Microtubule-Associated Proteins Transcription Factors Transcription Factor TFIIH Class III Phosphatidylinositol 3-Kinases TOR Serine-Threonine Kinases Vacuolar Sorting Protein VPS15 Autophagy-Related Protein 7
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Nemazanyy Ivan
Inserm, U845, Paris, France.
Blaauw Bert
Paolini Cecilia
Caillaud Catherine
Protasi Feliciano
Mueller Amelie
Proikas-Cezanne Tassula
Russell Ryan C
Guan Kun-Liang
Nishino Ichizo
Sandri Marco
Pende Mario
Panasyuk Ganna
Supplementary Concepts
Vacuolar myopathy (Disease)
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Article Info
Journal
EMBO molecular medicine
Abbr.
EMBO Mol Med
ISSN
1757-4684
DOI
10.1002/emmm.201202057
Published
2013-06-00
Epub
2013-00-30
Pages
870-90
Language
English
Region
England
NLM ID
101487380
PMCID
PMC3779449
Subset
IM
Grants
Telethon · GGP08153 · Italy
NIGMS NIH HHS · R01 GM051586 · United States
External Links
PubMed source DOI: 10.1002/emmm.201202057 PMC Full Text View journal details
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