Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease

Tokiko Fukuda, Lindsay Ewan, Martina Bauer, Robert J. Mattaliano, Kristien Zaal, Evelyn Ralston, Paul H. Plotz, Nina Raben

Research output: Contribution to journalArticlepeer-review

221 Scopus citations


Objective: 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. Methods: 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. Results: 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. Interpretation: The vastly increased autophagic buildup may be responsible for skeletal muscle damage and prevent efficient trafficking of replacement enzyme to lysosomes.

Original languageEnglish (US)
Pages (from-to)700-708
Number of pages9
JournalAnnals of Neurology
Issue number4
StatePublished - Apr 2006
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)


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