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Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease.
Mol Ther 2006; 14(6):831-9MT

Abstract

Enzyme replacement therapy (ERT) became a reality for patients with Pompe disease, a fatal cardiomyopathy and skeletal muscle myopathy caused by a deficiency of glycogen-degrading lysosomal enzyme acid alpha-glucosidase (GAA). The therapy, which relies on receptor-mediated endocytosis of recombinant human GAA (rhGAA), appears to be effective in cardiac muscle, but less so in skeletal muscle. We have previously shown a profound disturbance of the lysosomal degradative pathway (autophagy) in therapy-resistant muscle of GAA knockout mice (KO). Our findings here demonstrate a progressive age-dependent autophagic buildup in addition to enlargement of glycogen-filled lysosomes in multiple muscle groups in the KO. Trafficking and processing of the therapeutic enzyme along the endocytic pathway appear to be affected by the autophagy. Confocal microscopy of live single muscle fibers exposed to fluorescently labeled rhGAA indicates that a significant portion of the endocytosed enzyme in the KO was trapped as a partially processed form in the autophagic areas instead of reaching its target--the lysosomes. A fluid-phase endocytic marker was similarly mistargeted and accumulated in vesicular structures within the autophagic areas. These findings may explain why ERT often falls short of reversing the disease process and point toward new avenues for the development of pharmacological intervention.

Authors+Show Affiliations

Arthritis and Rheumatism Branch, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

17008131

Citation

Fukuda, Tokiko, et al. "Autophagy and Mistargeting of Therapeutic Enzyme in Skeletal Muscle in Pompe Disease." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 14, no. 6, 2006, pp. 831-9.
Fukuda T, Ahearn M, Roberts A, et al. Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease. Mol Ther. 2006;14(6):831-9.
Fukuda, T., Ahearn, M., Roberts, A., Mattaliano, R. J., Zaal, K., Ralston, E., ... Raben, N. (2006). Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease. Molecular Therapy : the Journal of the American Society of Gene Therapy, 14(6), pp. 831-9.
Fukuda T, et al. Autophagy and Mistargeting of Therapeutic Enzyme in Skeletal Muscle in Pompe Disease. Mol Ther. 2006;14(6):831-9. PubMed PMID: 17008131.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease. AU - Fukuda,Tokiko, AU - Ahearn,Meghan, AU - Roberts,Ashley, AU - Mattaliano,Robert J, AU - Zaal,Kristien, AU - Ralston,Evelyn, AU - Plotz,Paul H, AU - Raben,Nina, Y1 - 2006/09/27/ PY - 2006/05/24/received PY - 2006/08/06/revised PY - 2006/08/17/accepted PY - 2006/9/30/pubmed PY - 2007/1/31/medline PY - 2006/9/30/entrez SP - 831 EP - 9 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 14 IS - 6 N2 - Enzyme replacement therapy (ERT) became a reality for patients with Pompe disease, a fatal cardiomyopathy and skeletal muscle myopathy caused by a deficiency of glycogen-degrading lysosomal enzyme acid alpha-glucosidase (GAA). The therapy, which relies on receptor-mediated endocytosis of recombinant human GAA (rhGAA), appears to be effective in cardiac muscle, but less so in skeletal muscle. We have previously shown a profound disturbance of the lysosomal degradative pathway (autophagy) in therapy-resistant muscle of GAA knockout mice (KO). Our findings here demonstrate a progressive age-dependent autophagic buildup in addition to enlargement of glycogen-filled lysosomes in multiple muscle groups in the KO. Trafficking and processing of the therapeutic enzyme along the endocytic pathway appear to be affected by the autophagy. Confocal microscopy of live single muscle fibers exposed to fluorescently labeled rhGAA indicates that a significant portion of the endocytosed enzyme in the KO was trapped as a partially processed form in the autophagic areas instead of reaching its target--the lysosomes. A fluid-phase endocytic marker was similarly mistargeted and accumulated in vesicular structures within the autophagic areas. These findings may explain why ERT often falls short of reversing the disease process and point toward new avenues for the development of pharmacological intervention. SN - 1525-0016 UR - https://www.unboundmedicine.com/medline/citation/17008131/Autophagy_and_mistargeting_of_therapeutic_enzyme_in_skeletal_muscle_in_Pompe_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(06)01638-8 DB - PRIME DP - Unbound Medicine ER -