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Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease.
Autophagy 2010; 6(8):1078-89A

Abstract

Autophagy, an intracellular system for delivering portions of cytoplasm and damaged organelles to lysosomes for degradation/recycling, plays a role in many physiological processes and is disturbed in many diseases. We recently provided evidence for the role of autophagy in Pompe disease, a lysosomal storage disorder in which acid alphaglucosidase, the enzyme involved in the breakdown of glycogen, is deficient or absent. Clinically the disease manifests as a cardiac and skeletal muscle myopathy. The current enzyme replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from skeletal muscle. In our Pompe model, the poor muscle response to therapy is associated with the presence of pools of autophagic debris. To clear the fibers of the autophagic debris, we have generated a Pompe model in which an autophagy gene, Atg7, is inactivated in muscle. Suppression of autophagy alone reduced the glycogen level by 50–60%. Following ERT, muscle glycogen was reduced to normal levels, an outcome not observed in Pompe mice with genetically intact autophagy. The suppression of autophagy, which has proven successful in the Pompe model, is a novel therapeutic approach that may be useful in other diseases with disturbed autophagy.

Authors+Show Affiliations

Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. rabenn@mail.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20861693

Citation

Raben, Nina, et al. "Suppression of Autophagy Permits Successful Enzyme Replacement Therapy in a Lysosomal Storage Disorder--murine Pompe Disease." Autophagy, vol. 6, no. 8, 2010, pp. 1078-89.
Raben N, Schreiner C, Baum R, et al. Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease. Autophagy. 2010;6(8):1078-89.
Raben, N., Schreiner, C., Baum, R., Takikita, S., Xu, S., Xie, T., ... Plotz, P. H. (2010). Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease. Autophagy, 6(8), pp. 1078-89. doi:10.4161/auto.6.8.13378.
Raben N, et al. Suppression of Autophagy Permits Successful Enzyme Replacement Therapy in a Lysosomal Storage Disorder--murine Pompe Disease. Autophagy. 2010;6(8):1078-89. PubMed PMID: 20861693.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease. AU - Raben,Nina, AU - Schreiner,Cynthia, AU - Baum,Rebecca, AU - Takikita,Shoichi, AU - Xu,Sengen, AU - Xie,Tao, AU - Myerowitz,Rachel, AU - Komatsu,Masaaki, AU - Van der Meulen,Jack H, AU - Nagaraju,Kanneboyina, AU - Ralston,Evelyn, AU - Plotz,Paul H, PY - 2010/9/24/entrez PY - 2010/9/24/pubmed PY - 2011/3/3/medline SP - 1078 EP - 89 JF - Autophagy JO - Autophagy VL - 6 IS - 8 N2 - Autophagy, an intracellular system for delivering portions of cytoplasm and damaged organelles to lysosomes for degradation/recycling, plays a role in many physiological processes and is disturbed in many diseases. We recently provided evidence for the role of autophagy in Pompe disease, a lysosomal storage disorder in which acid alphaglucosidase, the enzyme involved in the breakdown of glycogen, is deficient or absent. Clinically the disease manifests as a cardiac and skeletal muscle myopathy. The current enzyme replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from skeletal muscle. In our Pompe model, the poor muscle response to therapy is associated with the presence of pools of autophagic debris. To clear the fibers of the autophagic debris, we have generated a Pompe model in which an autophagy gene, Atg7, is inactivated in muscle. Suppression of autophagy alone reduced the glycogen level by 50–60%. Following ERT, muscle glycogen was reduced to normal levels, an outcome not observed in Pompe mice with genetically intact autophagy. The suppression of autophagy, which has proven successful in the Pompe model, is a novel therapeutic approach that may be useful in other diseases with disturbed autophagy. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/20861693/Suppression_of_autophagy_permits_successful_enzyme_replacement_therapy_in_a_lysosomal_storage_disorder__murine_Pompe_disease_ L2 - http://www.tandfonline.com/doi/full/10.4161/auto.6.8.13378 DB - PRIME DP - Unbound Medicine ER -