Apoptosis regulating Bcl-2 protein family at the mitochondrial membrane: Its function in neurodegeneration

Programmed cell death (apoptosis) is essential for human life. Its intrinsic pathway is regulated by opposing members of the Bcl-2 protein family who tightly controls mitochondrial outer membrane (MOM) pore formation and release of apoptotic factors triggering cell death. Escape of apoptosis by blocking cell killing Bax (a Bcl-2 member) protein induced MOM perforation is an important hallmark of many cancers. Here, our main hypothesis is that in neurodegenerative disorders premature neuronal death occurs through blocking cell-protecting Bcl-2 protein (and relatives) by misfolded amyloidogenic proteins causing the release of MOM pore forming Bax from the protective, membrane embedded Bcl-2/Bax complex. Here, we seek to prove our hypothesis that the amyloidogenic apoSOD1 protein, a key culprit in the fatal motor neuron disease amyotrophic lateral sclerosis, ALS (3), can inhibit Bcl-2 directly and/or dissociate the Bcl-2/Bax complex at the MOM with the consequence that Bax gets released and causes neuronal cell death via MOM perforation. This is a potential key mechanism in ALS and other neurodegenerative disorders that is hitherto unexplored. Therefore, we will use NR to provide a molecular and kinetic insight into the interference of apoSOD1 in the recognition of Bcl-2 and sequestering of Bax from its Bcl-2 complex at the membrane level.