Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease
Article first published online: 10 MAR 2006
Copyright © 2006 American Neurological Association
Annals of Neurology
Volume 59, Issue 4, pages 700–708, April 2006
How to Cite
Fukuda, T., Ewan, L., Bauer, M., Mattaliano, R. J., Zaal, K., Ralston, E., Plotz, P. H. and Raben, N. (2006), Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Ann Neurol., 59: 700–708. doi: 10.1002/ana.20807
- Issue published online: 24 MAR 2006
- Article first published online: 10 MAR 2006
- Manuscript Accepted: 26 DEC 2005
- Manuscript Revised: 15 DEC 2005
- Manuscript Received: 12 SEP 2005
- Intramural Research Program of the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS])
To understand the mechanisms of skeletal muscle destruction and resistance to enzyme replacement therapy in Pompe disease, a deficiency of lysosomal acid α-glucosidase (GAA), in which glycogen accumulates in lysosomes primarily in cardiac and skeletal muscles.
We have analyzed compartments of the lysosomal degradative pathway in GAA-deficient myoblasts and single type I and type II muscle fibers isolated from wild-type, untreated, and enzyme replacement therapy–treated GAA knock-out mice.
Studies in myoblasts from GAA knock-out mice showed a dramatic expansion of vesicles of the endocytic/autophagic pathways, decreased vesicular movement in overcrowded cells, and an acidification defect in a subset of late endosomes/lysosomes. Analysis by confocal microscopy of isolated muscle fibers demonstrated that the consequences of the lysosomal glycogen accumulation are strikingly different in type I and II muscle fibers. Only type II fibers, which are the most resistant to therapy, contain large regions of autophagic buildup that span the entire length of the fibers.
The vastly increased autophagic buildup may be responsible for skeletal muscle damage and prevent efficient trafficking of replacement enzyme to lysosomes. Ann Neurol 2006