Why Gleevec Could Make Kids Hypersensitive To Smell

The gene Abl, a target of the anti-cancer drug Gleevec, is required for the correct development of the olfactory system.

AsianScientist (Mar. 13, 2020) – A study in mice suggests that the disruption of a gene called Abl1 could cause hypersensitivity to smells that often accompanies neurodevelopmental disorders such as autism spectrum disorder. Their findings are published in Cell Reports.

Sensory circuits are extensively developed in the year following birth, before the formation of cognitive or verbal neural circuits in the brain. Cognitive and sensory defects may ensue if inhibitory neural circuits are not generated during this formative period. However, the underlying genetics of inhibitory neural circuit development remain poorly documented.

In the present study, a team of scientists led by Professor Cheil Moon of the Daegu Gyeongbuk Institute of Science and Technology, South Korea, have found that the gene Abl1 is expressed at high levels during the early development of inhibitory neurons in the mouse olfactory bulb. They also learned that if the expression or activation of Abl1 is inhibited, inhibitory neurons exhibit structural and functional defects.

The researchers noted that Abl1 is also known to cause cancer. If chronic myelogenous leukemia patients aged 2 to 9 with active brain development are given the anti-cancer drug Gleevec (Imatinib), an Abl1 deactivator, more than 60 percent of them show sensory related-side effects such as olfactory hallucination. In mice, the research team confirmed that the inhibition of Abl1 with Gleevec greatly increased olfactory sensitivity.

Further experiments using proteomics revealed that Abl1 temporarily phosphorylated doublecortin (Dcx), a cytoskeletal protein that plays a crucial role in the structural development of brain. This suggested that Abl1 regulates the dynamics of microtubules with a new signal transmission system between Abl1 and Dcx.

“We have found a very important clue to understand the mechanism of hypersensitivity appearing in neurodevelopmental disorder or cancer,” said Moon. “We hope to see follow-up research to overcome other sensory disorders based on our findings.”

The article can be found at: Kim et al. (2020) Timely Inhibitory Circuit Formation Controlled by Abl1 Regulates Innate Olfactory Behaviors in Mouse.


Source: Daegu Gyeongbuk Institute of Science and Technology; Photo: Shutterstock.
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