J.D.L. and J.S. contributed equally to this work.
β-Amyloid is a substrate of autophagy in sporadic inclusion body myositis
Version of Record online: 27 APR 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 61, Issue 5, pages 476–483, May 2007
How to Cite
Lünemann, J. D., Schmidt, J., Schmid, D., Barthel, K., Wrede, A., Dalakas, M. C. and Münz, C. (2007), β-Amyloid is a substrate of autophagy in sporadic inclusion body myositis. Ann Neurol., 61: 476–483. doi: 10.1002/ana.21115
- Issue online: 27 APR 2007
- Version of Record online: 27 APR 2007
- Manuscript Accepted: 2 FEB 2007
- Manuscript Revised: 25 JAN 2007
- Manuscript Received: 13 OCT 2006
- Arnold and Mabel Beckman Foundation
- Alexandrine and Alexander Sinsheimer Foundation
- Burroughs Wellcome Fund
- Dana Foundation's Neuroimmunology program
- National Cancer Institute. Grant Numbers: R01CA108609, R01CA101741
- NIH (National Institute of Allergy and Infectious Diseases). Grant Number: RFP-NIH-NIAID-DAIDS-BAA-06-19
- Foundation for the National Institutes of Health (Grand Challenges in Global Health)
- Institutional Clinical and Translational Science Award (to the Rockefeller University Hospital)
- Dana Foundation and Irvington Institute's Human Immunology Fellowship. Grant Number: U54RR023419
- Pilot Study Funds of the Institutional Clinical and Translational Science Award (to the Rockefeller University Hospital). Grant Number: 1UL1RR024143
- University of Göttingen
- Association Francaise contre les Myopathies (AFM). Grant Number: AM/NM/2006.1377/12087
- Predoctoral fellowship from the Schering foundation
- Volkswagen Stiftung. Grant Number: ZN1294
Sporadic Inclusion Body Myositis (sIBM) is the most common acquired muscle disease in patients above 50 years of age. Apart from inflammation in the skeletal muscle, overexpression of amyloid precursor protein (APP) and intracellular accumulation of its proteolytic fragment β-amyloid play a central role in the pathogenesis of sIBM. In neurodegenerative disorders, similar aggregations of aberrant proteins have recently been shown to be susceptible to autophagic degradation. Therefore, we analyzed macroautophagy of APP in human muscle cell lines and sIBM muscle biopsies.
Colocalization of APP with the essential autophagy protein Atg8/LC3, which associates with preautophagosomal and autophagosomal membranes via lipidation, was analyzed in the CCL-136 muscle cell line and muscle biopsies by immunofluorescence. While APP was visualized with specific antibodies in the muscle cell line and in tissue sections. Atg8/LC3 localization was analyzed after GFP-Atg8/LC3 transfection or with an Atg8/LC3 specific antiserum, respectively.
We demonstrate here that Atg8/LC3 colocalizes with APP in cultured human muscle cells. In addition, APP/β-amyloid-containing autophagosomes can be observed at increased frequency in muscle fibers of sIBM muscle biopsies, but not in non-myopathic muscle or non-vacuolated myopathic controls. APP/β-amyloid and Atg8/LC3 double-positive compartments were almost exclusively observed in degenerating muscle fibers of the type II (fast-twitching) and were in part associated with overexpression of major histocompatibility complex (MHC) class I and II on myofibers and invasion by CD4+ and CD8+ cells.
These findings indicate that APP/β-amyloid is targeted for lysosomal degradation via macroautophagy and suggest that the autophagy pathway should be explored for its potential therapeutic merit in sIBM. Ann Neurol 2007;61:476–483