title: Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis.
abstract: Pharmacological activation of autophagy is becoming an attractive strategy to induce the selective degradation of aggregate-prone proteins. Recent evidence also suggests that autophagy impairment may underlie the pathogenesis of several neurodegenerative diseases. Mutations in the gene encoding SOD1 (superoxide disumutase 1) trigger familial amyotrophic lateral sclerosis (ALS), inducing its misfolding and aggregation and the progressive loss of motoneurons. It is still under debate whether autophagy has a protective or detrimental role in ALS. Here we evaluate the impact of BECN1/Beclin 1, an essential autophagy regulator, in ALS. BECN1 levels were upregulated in both cells and animals expressing mutant SOD1. To evaluate the impact of BECN1 to the pathogenesis of ALS in vivo, we generated mutant SOD1 transgenic mice heterozygous for Becn1. We observed an unexpected increase in life span of mutant SOD1 transgenic mice haploinsufficient for Becn1 compared with littermate control animals. These effects were accompanied by enhanced accumulation of SQSTM1/p62 and reduced levels of LC3-II, and an altered equilibrium between monomeric and oligomeric mutant SOD1 species in the spinal cord. At the molecular level, we detected an abnormal interaction of mutant SOD1 with the BECN1-BCL2L1 complex that may impact autophagy stimulation. Our data support a dual role of BECN1 in ALS and depict a complex scenario in terms of predicting the effects of manipulating autophagy in a disease context.
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell (CEMC); Program of Cellular and Molecular Biology; Institute of Biomedical Sciences; University of Chile.
authors.forename: Melissa
authors.initials: M
authors.lastname: Nassif
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell (CEMC); Program of Cellular and Molecular Biology; Institute of Biomedical Sciences; University of Chile.
authors.forename: Vicente
authors.initials: V
authors.lastname: Valenzuela
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell (CEMC); Program of Cellular and Molecular Biology; Institute of Biomedical Sciences; University of Chile.
authors.forename: Diego
authors.initials: D
authors.lastname: Rojas-Rivera
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Neurounion Biomedical Foundation; Santiago, Chile.
authors.forename: René
authors.initials: R
authors.lastname: Vidal
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Neurounion Biomedical Foundation; Santiago, Chile.
authors.forename: Soledad
authors.initials: S
authors.lastname: Matus
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell (CEMC); Program of Cellular and Molecular Biology; Institute of Biomedical Sciences; University of Chile.
authors.forename: Karen
authors.initials: K
authors.lastname: Castillo
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell (CEMC); Program of Cellular and Molecular Biology; Institute of Biomedical Sciences; University of Chile.
authors.forename: Yerko
authors.initials: Y
authors.lastname: Fuentealba
authors.affiliation: INSERM U848; Villejuif, France; Metabolomics and Cell Biology Platforms; Institut Gustave Roussy; Villejuif, France; Equipe 11 labellisée par la Ligue contre le Cancer; Centre de Recherche des Cordeliers; Paris, France; Pôle de Biologie; Hôpital Européen Georges Pompidou; Paris, France; Université Paris Descartes; Sorbonne Paris Cité; Paris, France.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Department of Internal Medicine and Howard Hughes Medical Institute; UT Southwestern Medical Center; Dallas, TX USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell (CEMC); Program of Cellular and Molecular Biology; Institute of Biomedical Sciences; University of Chile; Neurounion Biomedical Foundation; Santiago, Chile; Department of Immunology and Infectious Diseases; Harvard School of Public Health; Boston, MA USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000473:pathology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001343:Autophagy; D000071186:Beclin-1; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D018390:Gene Targeting; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D066329:Protein Aggregates; D011485:Protein Binding; D055503:Protein Multimerization; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D015415:Biomarkers; D050505:Mutant Proteins; D066329:Protein Aggregates; D051020:bcl-X Protein; D013482:Superoxide Dismutase
keywords: ALS; Beclin 1; SOD1; autophagy; neurodegenerative disease