title: Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis.
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.
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-machi, Yonago 683-8503, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takamura
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.forename: Kenya
authors.initials: K
authors.lastname: Kajimaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Otsuka
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071186:Beclin-1; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D002478:Cells, Cultured; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000378:metabolism; D016537:Gangliosidosis, GM1 / Q000235:genetics / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology*; D010269:Paraquat / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D001616:beta-Galactosidase / Q000172:deficiency
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D004791:Enzyme Inhibitors; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D011506:Proteins; D005677:G(M1) Ganglioside; C025946:3-methyladenine; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D001616:beta-Galactosidase; D000225:Adenine; D010269:Paraquat