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

EMBO Molecular Medicine

Ivan Nemazanyy⁶  Bert Blaauw¹  Cecilia Paolini⁴  Catherine Caillaud⁶  Feliciano Protasi⁴  Amelie Mueller⁵  Tassula Proikas-Cezanne⁵  Ryan C. Russell⁷  Kun-Liang Guan⁷  Ichizo Nishino²  Marco Sandri¹  Mario Pende³ 

[1] Venetian Institute of Molecular Medicine, Padova, Italy;National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan;E-mail address: 关键词: autophagy;    human disease;    lysosomal storage disease;    mouse model;    mTOR signalling;   

DOI  :  10.1002/emmm.201202057

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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