The mammalian brain has a limited regenerative capacity. Therefore, the survival of neurons is essential to maintain the integrity of neural circuits and ensure proper brain function. Now, an article, recently published by the journal Neuron, identifies the genetic mechanism responsible for neuronal longevity.

In their work, scientists from different American universities, led by Sika Zheng of the University of California at Riverside, examined the process of programmed cell death, known as apoptosis. After exhaustive analysis of 1821 genes involved in this pathway, they turned their attention to a small sequence of Bak1, microexon number 5.

The exons of a gene contain the information necessary to make its protein. However, the same gene can give rise to different proteins by combining their exons. This occurs during alternative splicing, or splicing. In neurons, loss of microexon 5 results in an active form of Bak1 that promotes cell death. In contrast, the inclusion of this microexon inhibits the synthesis of Bak1.

Interestingly, Bak1 is remarkably expressed in embryonic brain tissue. This stage is characterized by neurogenesis, or generation of new neurons, from precursor stem cells, and apoptosis guarantees the elimination of excess synapses. However, neurons become resistant to programmed death as they mature, a fact that coincides with an increase in the presence of microexon 5.

In order to confirm the role of the small sequence, the researchers removed it from the murine genome. As a result, the number of differentiated neurons decreased markedly. Likewise, the mice died at 4 days of age. The absence of breast milk in the offspring’s stomach suggests that neuronal death would affect their ability to feed.

For Zeng and his collaborators, the finding evidences the temporal program by which alternative splicing regulates neuronal apoptosis. Likewise, it corroborates that, despite the important role it plays during development, the attenuation of programmed death allows the survival of the brain and the organism in the long term. In the future, the researchers will evaluate if the mechanism participates in the neurodegeneration process, in disorders such as Alzheimer’s.

Marta Pulido Salgado

Reference: “Developmental attenuation of neuronal apoptosis by neural-specific splicing of Bak1 microexon”, by L. Lin et al., In Neuron; 107: pages 1-17, advanced internet publication on July 24, 2020.