g(m1)-ganglioside and 3-methyladenine

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.

Topics: Adenine; Adenosine Triphosphate; Animals; Apoptosis Regulatory Proteins; Astrocytes; Autophagy; Beclin-1; beta-Galactosidase; Brain; Cells, Cultured; Disease Models, Animal; Electron Transport Complex IV; Enzyme Inhibitors; G(M1) Ganglioside; Gangliosidosis, GM1; Lysosomes; Mice; Mice, Knockout; Microtubule-Associated Proteins; Mitochondria; Paraquat; Protein Kinases; Proteins; Signal Transduction; TOR Serine-Threonine Kinases