Figure 8. Working model. (A) In a normal condition, BECN1 is inhibited by a direct interaction with BCL2 or BCL2L1 anti-apoptotic proteins. Once autophagy is triggered, BCL2 or BCL2L1 are released from BECN1 and the PtdIns3K (whose catalytic subunit is PIK3C3) is activated, resulting in formation of autophagosomes and downstream autophagy-mediated degradation of cargoes. (B) In ALS, the expression of mutant SOD1 leads to 2 possibilities: a formation of a triple complex between SOD1 and the BECN1-BCL2L1 complex or to an abnormal association with the BECN1 and BCL2L1 complex, destabilizing the interaction leading to abnormal autophagy levels. These pathological effects may be attenuated by the reduction of BECN1 levels in BECN1 heterozygous animals, which may normalize autophagy activity. In addition, mutant SOD1 aggregates are substrates of autophagy-mediated degradation.