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Review
. 2021 Jan;28(1):108-122.
doi: 10.1038/s41418-020-00654-2. Epub 2020 Nov 8.

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

James M Pemberton  1   2 , Justin P Pogmore  1   3 , David W Andrews  4   5   6
Affiliations
Review

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

James M Pemberton et al. Cell Death Differ. 2021 Jan.

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.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Different stressors/ damage (indicated by a red “X”) induce the transcription and translation of PUMA, resulting in activation of BAX, cytochrome c release and subsequent caspase activation.
In neuronal apoptosis it remains uncertain if PUMA activates BAX directly or indirectly. Unknown mechanisms are indicated by a “?”.
Fig. 2
Fig. 2. Local deprivation of trophic factor(s) from axons results in a retrograde signal to upregulate transcription of puma. Increased PUMA expression results in either direct or indirect activation of BAX, induction of caspase activation and subsequent degeneration of the axon.
However, there are many unknowns in the regulation of selective degradation of axons including: the location of MOMP, how caspase-9 is activated, and how neuronal cell bodies remain alive when PUMA is expressed and caspases activated. Unknown mechanisms are indicated by a “?”. The numbers “1” and “2” indicate the extension of activation and inhibition signals down the axon, respectively.
Fig. 3
Fig. 3. Rationale for the development of BAX inhibitors.
Upstream signaling pathways converge at the MOM with BAX activation as the commitment step in apoptosis. Preventing caspase activation is not sufficient as MOMP causes the release of pro-apoptotic proteins that can lead to caspase independent cell death.
Fig. 4
Fig. 4. The BCL-2 family proteins PUMA and BAX regulate axon degeneration and apoptosis.
This unique reliance on only two proteins affords the possibility of pharmacological inhibition to prevent both process from occurring with minimal effects in other tissues. However, detailed understanding of the mechanism(s) of PUMA and BAX induced MOMP and necroptosis are first required.
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