title: Endoplasmic reticulum stress induces autophagy through activation of p38 MAPK in fibroblasts from Pompe disease patients carrying c.546G>T mutation.
abstract: Pompe disease (glycogen storage disease type II) is an autosomal recessive myopathic disorder arising from the deficiency of lysosomal acid α-glucosidase (GAA). Activation of autophagy is a key pathophysiological feature in skeletal muscle fibers and fibroblasts from patients with Pompe disease. The accumulation of autophagic vacuoles has been shown to interfere with the efficacy of enzyme replacement therapy with recombinant human GAA. However, the induction mechanism of autophagy in Pompe disease is still unclear. In this study, we show that misfolded GAA-induced endoplasmic reticulum (ER) stress triggers autophagy in a manner regulated by p38 MAPK signaling pathways in fibroblasts from late-onset patients with Pompe disease. By studying normal fibroblasts and patient fibroblasts carrying a c.546G>T mutation, we uncovered that mutant GAA was rapidly degraded by proteasome. In addition, we found both activation of ER stress response and autophagy in these patient fibroblasts. Treatment with N-butyl-deoxynojirimycin (NB-DNJ), which acts as a pharmacological chaperone for certain mutant forms of GAA, led to attenuation of not only ER stress, but also autophagy in patient fibroblasts. Levels of phosphorylated p38 MAPK observed in patient fibroblasts were decreased after treatment with NB-DNJ. The autophagic response in patient fibroblasts was also negatively regulated by treatment with the p38 MAPK inhibitor SB203580. These findings define a critical role for ER stress in the activation of autophagy due to GAA mutation, and provide evidence that chaperone therapy may be a useful treatment for alleviation of autophagy in Pompe disease patients carrying a chaperon-responsive mutation.
authors: Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors: Yohta
authors: Y
authors: Shimada
authors: Hiroshi
authors: H
authors: Kobayashi
authors: Shiho
authors: S
authors: Kawagoe
authors: Katsuhiko
authors: K
authors: Aoki
authors: Eiko
authors: E
authors: Kaneshiro
authors: Hiromi
authors: H
authors: Shimizu
authors: Yoshikatsu
authors: Y
authors: Eto
authors: Hiroyuki
authors: H
authors: Ida
authors: Toya
authors: T
authors: Ohashi
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006009:Glycogen Storage Disease Type II / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D017510:Protein Folding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D000520:alpha-Glucosidases / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D010750:Phosphoproteins; D020033:Protein Isoforms; D017485:1-Deoxynojirimycin; C059896:miglustat; D048051:p38 Mitogen-Activated Protein Kinases; C509951:GAA protein, human; D000520:alpha-Glucosidases