Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis
Authors: Diego Rojas-Rivera
Yerko Fuentealba
René Vidal
Karen Castillo
Beth Levine
Melissa Nassif
Vicente Valenzuela
Claudio Hetz
Guido Kroemer
Soledad Matus
Journal: Autophagy (2014)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: ALS; Beclin 1; SOD1; autophagy; neurodegenerative disease.
Affiliations: 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., Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Neurounion Biomedical Foundation; Santiago, Chile., 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., Department of Internal Medicine and Howard Hughes Medical Institute; UT Southwestern Medical Center; Dallas, TX USA., 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.

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. 

Retracted: No

PubPeer comments:
 The Western blot results of Flotillin-1 and TSG101 in Figure 1B seemingly used the same membrane which was exposed different time. Also, the results of STAT1 in Figure 1D and in Figure 6B seemingly be spliced.![file] ![file] ![file] , 
 Dear sir, I appreciate your concern. The original data has been carefully reviewed. The bands are all correct. The original data can be found below. Please feel free to contact me if you have any further questions. , 
 #2 The original bands will shown below. , 
 #1 The original bands that your concerned are shown here. They are different from each other! ![file] ,