Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis

Ayumi Takamura; Katsumi Higaki; Kenya Kajimaki; Susumu Otsuka; Haruaki Ninomiya; Junichiro Matsuda; Kousaku Ohno; Yoshiyuki Suzuki; Eiji Nanba

doi:10.1016/j.bbrc.2007.12.187

Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis

Biochem Biophys Res Commun. 2008 Mar 14;367(3):616-22. doi: 10.1016/j.bbrc.2007.12.187. Epub 2008 Jan 9.

Authors

Ayumi Takamura¹, Katsumi Higaki, Kenya Kajimaki, Susumu Otsuka, Haruaki Ninomiya, Junichiro Matsuda, Kousaku Ohno, Yoshiyuki Suzuki, Eiji Nanba

Affiliation

¹ Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-machi, Yonago 683-8503, Japan.

PMID: 18190792
DOI: 10.1016/j.bbrc.2007.12.187

Abstract

G(M1)-gangliosidosis is an autosomal recessive lysosomal lipid storage disorder, caused by mutations of the lysosomal beta-galactosidase (beta-gal) and results in the accumulation of G(M1). The underlying mechanisms of neurodegeneration are poorly understood. Here we demonstrate increased autophagy in beta-gal-deficient (beta-gal(-/-)) mouse brains as evidenced by elevation of LC3-II and beclin-1 levels. Activation of autophagy in the beta-gal(-/-) brain was found to be accompanied with enhanced Akt-mTOR and Erk signaling. In addition, the mitochondrial cytochrome c oxidase activity was significantly decreased in brains and cultured astrocytes from beta-gal(-/-) mouse. Mitochondria isolated from beta-gal(-/-) astrocytes were morphologically abnormal and had a decreased membrane potential. These cells were more sensitive to oxidative stress than wild type cells and this sensitivity was suppressed by ATP, an autophagy inhibitor 3-methyladenine and a pan-caspase inhibitor z-VAD-fmk. These results suggest activation of autophagy leading to mitochondrial dysfunction in the brain of G(M1)-gangliosidosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives
Adenine / pharmacology
Adenosine Triphosphate / pharmacology
Animals
Apoptosis Regulatory Proteins
Astrocytes / drug effects
Astrocytes / metabolism
Astrocytes / pathology
Autophagy* / drug effects
Autophagy* / genetics
Beclin-1
Brain / pathology*
Brain / ultrastructure
Cells, Cultured
Disease Models, Animal
Electron Transport Complex IV / metabolism
Enzyme Inhibitors / pharmacology
G(M1) Ganglioside / metabolism
Gangliosidosis, GM1 / genetics
Gangliosidosis, GM1 / pathology*
Lysosomes / metabolism
Mice
Mice, Knockout
Microtubule-Associated Proteins / metabolism
Mitochondria / enzymology
Mitochondria / pathology*
Paraquat / pharmacology
Protein Kinases / metabolism
Proteins / metabolism
Signal Transduction / genetics
TOR Serine-Threonine Kinases
beta-Galactosidase / deficiency

Substances

Apoptosis Regulatory Proteins
Beclin-1
Becn1 protein, mouse
Enzyme Inhibitors
Map1lc3b protein, mouse
Microtubule-Associated Proteins
Proteins
G(M1) Ganglioside
3-methyladenine
Adenosine Triphosphate
Electron Transport Complex IV
Protein Kinases
mTOR protein, mouse
TOR Serine-Threonine Kinases
beta-Galactosidase
Adenine
Paraquat