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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.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
This work was funded by the Muscular Dystrophy Association and ALS Therapy Alliance; Millennium Institute no. P09-015-F, ACT1109; FONDEF D11I1007; FONDECYT no. 1140549, AD Association, CONICYT grant USA2013-0003, ECOS-CONICYT C13S02 (CH), postdoc fellow FONDECYT 3140110 (MN), 3130365 (DRR), and FONDECYT 11121524 (SM). VV received a CONICYT PhD fellowship no. 21120411. This work was also funded by NIH RO1 CA109618 (BL). GK is supported by the Ligue Nationale contre le Cancer, Agence Nationale pour la Recherche, European Commission (ArtForce), European Research Council, Institut National du Cancer (INCa), Cancéropôle Ile-de-France, Fondation Bettencourt-Schueller, AXA Chair for Longevity Research, LabEx Immuno-Oncology, and Paris Alliance of Cancer Research Institutes.
We are grateful to Dr Maria Chiara Maiuri and Dr Alfredo Criollo (INSERM U848 Villejuif, France) for their advice in assessing BECN1-BCL2L1 interaction. We thank Dr Julie Atkin (Florey Neuroscience Institutes, Australia) for providing SOD1-GFP constructs and Dr Thomas V O’Halloran (Northwestern University) for providing SOD1-MYC plasmids. We are thankful to Claudia Duran for advices in tissue deparaffinization protocol, Monica Flores for technical help, and Silke Escobar for mice care.