| 18190792 |
Takamura A, Higaki K, Kajimaki K, Otsuka S, Ninomiya H, Matsuda J, Ohno K, Suzuki Y, Nanba E: Enhanced autophagy and mitochondrial aberrations in murine G (M1)-gangliosidosis. Biochem Biophys Res Commun. 2008 Mar 14;367(3):616-22. Epub 2008 Jan 9.
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. |
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