Dataset Information

Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease.

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.

SUBMITTER: Raben N

PROVIDER: S-EPMC3039718 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease.

Raben Nina N Schreiner Cynthia C Baum Rebecca R Takikita Shoichi S Xu Sengen S Xie Tao T Myerowitz Rachel R Komatsu Masaaki M Van der Meulen Jack H JH Nagaraju Kanneboyina K Ralston Evelyn E Plotz Paul H PH

Autophagy 20101101 8

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. ...[more]

PMID: 20861693

Similar Datasets

Project description:INTRODUCTION:Lysosomal storage diseases (LSDs) are rare inherited metabolic diseases characterized by an abnormal accumulation of various toxic materials in the cells as a result of enzyme deficiencies leading to tissue and organ damage. Among clinical manifestations, cardiac diseases are particularly important in Pompe glycogen storage diseases (PD), in glycosphingolipidosis Fabry disease (FD), and mucopolysaccharidoses (MPS). Here, we evaluated the occurrence of aortopathy in knock out (KO) mouse models of three different LSDs, including PD, FD, and MPS IIIB. METHODS:We measured the aortic diameters in 15 KO male mice, 5 for each LSD: 5 GLA-/- mice for FD, 5 NAGLU-/- mice for MPS IIIB, 5 GAA-/- mice for PD, and 15 wild type (WT) mice: 5 for each strain. In order to compare the aortic parameters between KO and WT mice deriving from the same colonies, different diameters were echocardiographically measured: aortic annulus, aortic sinus, sino-tubular junction, ascending aorta, aortic arch and descending aorta. Storage material content and aortic defects of the KO mice were also analyzed by histology, when available. RESULTS:Compared to their correspondent WT mice: GAA-/- mice showed greater diameters of ascending aorta (1.61mm vs. 1.11mm, p-value = 0.01) and descending aorta (1.17mm vs 1.02mm, p-value 0.04); GLA-/- mice showed greater diameters of aortic annulus (1.35mm vs. 1.22mm, p-value = 0.01), sinus of Valsalva (1.6mm vs. 1.38mm, p-value<0.01), ascending aorta (1.57mm vs. 1.34mm, p-value<0.01), aortic arch (1.36mm vs. 1.22mm, p-value = 0.03) and descending aorta (1.29mm vs. 1.11mm, p-value<0.01); NAGLU-/- mice showed greater diameters of sinus of Valsalva (1.46mm vs. 1.31mm, p-value = 0.05), ascending aorta (1.42mm vs. 1.29mm, p-value<0.01), aortic arch (1.34mm vs. 1.28mm, p-value<0.01) and descending aorta (1.18mm vs. 1.1mm, p-value 0.01). CONCLUSIONS:We evaluated for the first time the aortic diameters in 3 LSD mouse models and identified different aortopathy patterns, in concordance with recent human findings. Our results are relevant in view of using KO mouse models for efficiently testing the efficacy of new therapies on distinct cardiovascular aspects of LSDs.

Dataset Information

Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease.

Publications

Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets