Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis

Melissa Nassif, Vicente Valenzuela, Diego Rojas-Rivera, René Vidal, Soledad Matus, Karen Castillo, Yerko Fuentealba, Guido Kroemer, Beth Levine, Claudio Hetz

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1256-1271
Number of pages16
Issue number7
StatePublished - Jul 2014


  • ALS
  • Autophagy
  • Beclin 1
  • Neurodegenerative disease
  • SOD1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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