Your body’s ‘bomb squad’ can protect your brain against tumors

A tumorous brain in fruit flies caused by retromer inactivation (right), compared to the normal fly brain (left). | Credit: Li, Wong et al. / eLife, 2018

Researchers have found how a molecule can help counter certain types of brain tumors by identifying and ‘disarming’ harmful proteins that are responsible for brain tumors. This study on fruit flies, was published recently in the journal eLife, and it could help scientists get insights into a potential, new treatment approach for brain tumors in future.

Most of the multicellular organisms have a one-way cell signaling pathway, known as Notch signaling, which is important for embryonic development. The correct establishment and maintenance of Notch signaling are crucial for making sure that there is a balance in the number of stem cells that occur in the body and brain.

“Abnormal activation of Notch signaling in neural progenitors – which send signals to neural stem cells – can cause an excess of these stem cells to occur in the brain, and this can in turn lead to brain tumor development,” explained Bo Li, co-first author of the study and also a PhD Candidate at Peking University, China. “However, the molecular mechanisms that prevent abnormal Notch signaling activation and potentially harmful decisions related to cell fate remain unclear.”

To try and answer this question, the research team conducted genetic and biochemical tests to study stem cells- called neuroblasts-which are present in the central brain region of fruit fly larvae. They especially looked at the retromer protein complex, which is responsible for transporting specific cargo proteins from endosomes (a type of membrane-bound compartment inside cells) to the cell surface.

The analysis showed that the retromer complex controls the Notch protein’s trafficking in neural progenitors. When this complex is inactive, Notch receptors aren’t activated properly, which transforms the progenitors into surplus amount of neural stem cells, which in turn increases the risk of developing brain tumor.

“We found that a sufficient amount of Notch protein needs to be destroyed in neural progenitors to maintain the one-way Notch signaling pathway between these progenitors and neural stem cells,” said co-first author Chouin Wong, a Graduate Student at Peking University.

“When an excess of Notch protein fails to be destroyed in neural progenitors, this is normally recognized by the retromer complex and is rapidly transported away from the endosomes inside cells. But when the retromer complex is inactive, this pool of Notch protein increases massively in the endosomes and is ‘ignited’ abnormally”, added Wong.

These results were behind the team proposing a model in which the retromer complex play the role of a kind of ‘bomb squad’ to get recapture and disarm the potentially harmful mass of incorrectly activated Notch receptors in a timely manner, which will aide in preventing the risk of brain tumors forming this way.

“In light of these findings, we believe further investigation into the regulatory mechanisms underlying Notch overactivation is necessary,” concluded Yan Song, senior author of the study and Principal Investigator at Peking University. “In particular, a deeper understanding of how to prevent abnormal Notch signaling activation in neural progenitors could potentially provide a new approach for treating brain tumors in future.”


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