Neuronal cell life, death, and axonal degeneration as regulated by the BCL-2 family proteins

Abstract

Axonal degeneration and neuronal cell death are fundamental processes in development and contribute to the pathology of neurological disease in adults. Both processes are regulated by BCL-2 family proteins which orchestrate the permeabilization of the mitochondrial outer membrane (MOM). MOM permeabilization (MOMP) results in the activation of pro-apoptotic molecules that commit neurons to either die or degenerate. With the success of small-molecule inhibitors targeting anti-apoptotic BCL-2 proteins for the treatment of lymphoma, we can now envision the use of inhibitors of apoptosis with exquisite selectivity for BCL-2 family protein regulation of neuronal apoptosis in the treatment of nervous system disease. Critical to this development is deciphering which subset of proteins is required for neuronal apoptosis and axon degeneration, and how these two different outcomes are separately regulated. Moreover, noncanonical BCL-2 family protein functions unrelated to the regulation of MOMP, including impacting necroptosis and other modes of cell death may reveal additional potential targets and/or confounders. This review highlights our current understanding of BCL-2 family mediated neuronal cell death and axon degeneration, while identifying future research questions to be resolved to enable regulating neuronal survival pharmacologically.

Loss of HCN2 in Dorsal Hippocampus of Young Adult Mice Induces Specific Apoptosis of the CA1 Pyramidal Neuron Layer

“…This emphasizes that interfering with the exquisitely regulated protein expression and distribution could lead to dramatic changes in neuronal homeostasis. Even though there are no reports on compensatory up-or downregulations of gene expression in HCN1 or HCN2 knock-out animals, the interference with gene expression at a certain time point during postnatal stages might have severe functional implications [50].…”

The role of Bcl-2 proteins in modulating neuronal Ca2+ signaling in health and in Alzheimer's disease

“…The antiapoptotic Bcl-2-family members, Bcl-X L and Bcl-w are present in mature neurons, whereas Bcl-2 is mostly expressed in the developing brain [100][101][102]. In the following part, we will briefly discuss the known functions of pro-and anti-apoptotic Bcl-2 family members in neurons and refer the reader to Pemberton et al for an extensive discussion [103].…”

“…The main proteins responsible for Bax activation in neurons are the BH3-only activators Bid, Bim, and Puma. For instance, single deletion of Puma prevents both neuronal apoptosis [103,105,106] and axon degeneration [107] in vitro and in a variety of neuronal cell types from…”

“…Journal Pre-proof both the central and peripheral nervous system. This suggests that BH3-only activators play a significant role in regulating neuronal MOMP [103]. The central role of Bax in neuronal apoptosis is illustrated by the observation that Bax KO mice do not exhibit developmental programmed cell death of dorsal root ganglion sensory neurons, superior cervical ganglion sympathetic neurons, or motoneurons (MNs) [108][109][110].…”

“…Journal Pre-proof consequently causes the activation of CREB and ERK transcriptional programs that regulate neurite extension [125]. A recent review of Pemberton et al further focuses on the regulation of axon degeneration and neuronal cell death by Bcl-2 proteins [103]. Additionally, overexpression of Bcl-2 protects motor neuron cell bodies from apoptosis in a progressive motor neuropathy mouse model.…”