Fig. 7

Model of SNARE protective pool to antagonize APOL1-induced toxicity. Schematic representation of the SNARE protective pool model as a strategy to evade APOL1 toxicity. (Left) Under typical conditions, SNARE proteins provide protection against APOL1 toxicity by binding APOL1 protein which localizes APOL1 to the ER and thus prevents it from forming pores in lysosomal membranes. The SNARE proteins in the protective pool effectively bind APOL1-G0 and prevent toxic effects even in the event of a second hit, be it genetic predisposition or environmental. (Right) SNARE protein binding affinity for APOL1 risk alleles (APOL1-RA; APOL1-G1 and APOL1-G2) is reduced, compared to APOL1-G0. Under typical conditions this is still largely sufficient. However, when a second hit occurs, the protective pool cannot offer adequate compensation. Once a certain threshold is breached this results in unbound APOL1-RA, which in turn locates to the lysosome, where it forms pores thereby causing lysosomal acidification and cytotoxicity. (Bottom right) This model implicates expanding the SNARE protective pool as a potential therapeutic strategy. For example, one could overexpress SNARE proteins (as was shown effective for Syx7, Ykt6, and Syb), or a SNARE-like molecule. The increased SNARE protective pool has greater ability to bind and capture APOL1-RA, and to compensate against a second hit. By preventing unbound APOL1-RA to escape and locate at the cell organelles, the enhanced pool can reduce (or even eliminate) APOL1 toxic effects