Involvement of Bcl-xL in Neuronal Function and Development

Julie Bas,Germain Gillet,Trang Nguyen

doi:10.3390/ijms22063202

Abstract

The B-cell lymphoma (Bcl-2) family of proteins are mainly known for their role in the regulation of apoptosis by preventing pore formation at the mitochondrial outer membrane and subsequent caspase activation. However, Bcl-2 proteins also have non-canonical functions, independent of apoptosis. Indeed, the cell death machinery, including Bcl-2 homologs, was reported to be essential for the central nervous system (CNS), notably with respect to synaptic transmission and axon pruning. Here we focused on Bcl-xL, a close Bcl-2 homolog, which plays a major role in neuronal development, as bclx knock out mice prematurely die at embryonic day 13.5, showing massive apoptosis in the CNS. In addition, we present evidence that Bcl-xL fosters ATP generation by the mitochondria to fuel high energy needs by neurons, and its contribution to synaptic transmission. We discuss how Bcl-xL might control local and transient activation of caspases in neurons without causing cell death. Consistently, Bcl-xL may contribute to morphological changes, such as sprouting and retractation of axon branches, in the context of CNS plasticity. Regarding degenerative diseases and aging, a better understanding of the numerous roles of the cell death machinery in neurons may have future clinical implications.

Highlights

The Bcl-2 family of proteins plays a major role in the regulation of apoptosis, a highly conserved programmed cell death process that eliminates unwanted cells, including damaged cells, which is essential during development [1]
Bcl-xL was reported to control SERCA expression, the underlying mechanism remains unknown [45]. Despite such interactions have not been documented in nerve cells as yet, these data raise the idea that the control of SERCA activity by Bcl-2 homologs, including Bcl-xL, may be important in neurons, fostering Ca2+ uptake in the endoplasmic reticulum (ER) lumen and contributing to shape Ca2+ peaks during neurotransmission
In a study investigating the role of the ubiquitin E3 ligase E6AP in autism, it was shown that E6AP expression activates caspase-3 through the inhibition of the X-linked inhibitor of apoptosis (XIAP) responsible for caspase-3 ubiquitination, leading to microtubule cleavage and disorganization of axonal arborization [57]

Summary

Introduction

The Bcl-2 family of proteins plays a major role in the regulation of apoptosis, a highly conserved programmed cell death process that eliminates unwanted cells, including damaged cells, which is essential during development [1]. The interactions between all of these proteins determine the formation of “pores” in the MOM as a consequence of the homodimerization of the multi-domain apoptosis accelerators Bax and Bak, leading to the release of pro-apoptotic factors from the mitochondria, including cytochrome c (Figure 1). Bcl-xL, one of in turnbeen leading to thetocleavage of a large number of downstream targets, and eventually to death [6] Beyond their highly documented apoptosis, proteins andstem cells thecell most studied anti-apoptotic. Thisformation reflects the of this process, the activation of caspases is independent of apoptosome [20].importance This non-apoptotic functions of the cell death machinery in the development of the CNS.

Mitochondria Are Crucial for Neuronal Functions and Bcl-xL Can Control Their

Bcl-xL Impacts on Neuron Development and Growth

Caspases Regulate Neuronal Plasticity

Bcl-x Caspase Crosstalk

Findings

Concluding Remarks