| RRC ID |
44096
|
| 著者 |
Nishiyama Y, Shimada Y, Yokoi T, Kobayashi H, Higuchi T, Eto Y, Ida H, Ohashi T.
|
| タイトル |
Akt inactivation induces endoplasmic reticulum stress-independent autophagy in fibroblasts from patients with Pompe disease.
|
| ジャーナル |
Mol Genet Metab
|
| Abstract |
Pompe disease (glycogen storage disease type II) is an autosomal recessive neuromuscular disorder arising from a deficiency of lysosomal acid α-glucosidase (GAA). Accumulation of autophagosomes is a key pathological change in skeletal muscle fibers and fibroblasts from patients with Pompe disease and is implicated in the poor response to enzyme replacement therapy (ERT). We previously found that mutant GAA-induced endoplasmic reticulum (ER) stress initiated autophagy in patient fibroblasts. However, the mechanism of induction of autophagy in fibroblasts from Pompe disease patients lacking ER stress remains unclear. In this study, we show that inactivated Akt induces ER stress-independent autophagy via mTOR suppression in patient fibroblasts. Activated autophagy as evidenced by increased levels of LC3-II and autophagic vesicles was observed in patient fibroblasts, whereas PERK phosphorylation reflecting the presence of ER stress was not observed in them. These patient fibroblasts showed decreased levels of not only phosphorylated Akt, but also phosphorylated p70 S6 kinase. Treatment with insulin, which acts as an activator of the Akt signaling pathway, resulted in increased phosphorylation of both Akt and p70 S6 kinase and suppression of autophagy in patient fibroblasts. In addition, following combination treatment with recombinant human GAA plus insulin, enhanced localization of the enzymes with lysosomes was observed in patient fibroblasts. These findings define a critical role of Akt suppression in the induction of autophagy in fibroblasts from patients with Pompe disease carrying an ER stress non-inducible mutation, and they provide evidence that insulin may potentiate the effect of ERT.
|
| 巻・号 |
107(3)
|
| ページ |
490-5
|
| 公開日 |
2012-11-1
|
| DOI |
10.1016/j.ymgme.2012.09.011
|
| PII |
S1096-7192(12)00352-6
|
| PMID |
23041259
|
| MeSH |
Autophagy / drug effects*
Cells, Cultured
Endoplasmic Reticulum / metabolism
Fibroblasts / drug effects
Fibroblasts / enzymology*
Fibroblasts / pathology
Gene Expression / drug effects
Glucose / metabolism
Glucose / pharmacology
Glycogen / metabolism
Glycogen Storage Disease Type II / enzymology*
Glycogen Storage Disease Type II / genetics
Glycogen Storage Disease Type II / pathology
Humans
Infant, Newborn
Insulin / metabolism
Insulin / pharmacology
Lysosomes / drug effects
Lysosomes / enzymology
Muscle, Skeletal / drug effects
Muscle, Skeletal / enzymology*
Muscle, Skeletal / pathology
Phagosomes / drug effects
Phagosomes / enzymology
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / genetics
Ribosomal Protein S6 Kinases, 70-kDa / genetics
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Signal Transduction / drug effects
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / genetics
alpha-Glucosidases / metabolism
alpha-Glucosidases / pharmacology
|
| IF |
4.17
|
| 引用数 |
13
|
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
GENETICS & HEREDITY
ENDOCRINOLOGY & METABOLISM
|
| リソース情報 |
| ヒト・動物細胞 |
|
