title: GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis.
abstract: GM1-ganglioside (GM1) is a major sialoglycolipid of neuronal membranes that, among other functions, modulates calcium homeostasis. Excessive accumulation of GM1 due to deficiency of lysosomal beta-galactosidase (beta-gal) characterizes the neurodegenerative disease GM1-gangliosidosis, but whether the accumulation of GM1 is directly responsible for CNS pathogenesis was unknown. Here we demonstrate that activation of an unfolded protein response (UPR) associated with the upregulation of BiP and CHOP and the activation of JNK2 and caspase-12 leads to neuronal apoptosis in the mouse model of GM1-gangliosidosis. GM1 loading of wild-type neurospheres recapitulated the phenotype of beta-gal-/- cells and activated this pathway by depleting ER calcium stores, which ultimately culminated in apoptosis. Activation of UPR pathways did not occur in mice double deficient for beta-gal and ganglioside synthase, beta-gal-/-/GalNAcT-/-, which do not accumulate GM1. These findings suggest that the UPR can be induced by accumulation of the sialoglycolipid GM1 and this causes a novel mechanism of neuronal apoptosis.
authors.affiliation: Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tessitore
authors.forename: Maria
authors.initials: M
authors.lastname: del P  Martin
authors.forename: Renata
authors.initials: R
authors.lastname: Sano
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Ma
authors.forename: Linda
authors.initials: L
authors.lastname: Mann
authors.forename: Angela
authors.initials: A
authors.lastname: Ingrassia
authors.forename: Eric D
authors.initials: ED
authors.lastname: Laywell
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Steindler
authors.forename: Linda M
authors.initials: LM
authors.lastname: Hendershot
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D005677:G(M1) Ganglioside / Q000378:metabolism*; D016537:Gangliosidosis, GM1 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D017350:N-Acetylgalactosaminyltransferases / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism; D001616:beta-Galactosidase / Q000172:deficiency / Q000235:genetics; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002118:Calcium; D053454:Caspase 12; D020169:Caspases; D000091342:Endoplasmic Reticulum Chaperone BiP; D005677:G(M1) Ganglioside; D006360:Heat-Shock Proteins; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D018832:Molecular Chaperones; D017350:N-Acetylgalactosaminyltransferases; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D001616:beta-Galactosidase; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C497250:Ddit3 protein, mouse; C506440:Casp12 protein, mouse