In:
eLife, eLife Sciences Publications, Ltd, Vol. 4 ( 2015-12-03)
Abstract:
An enzyme called PI3K is involved in a major signaling pathway that controls cell growth. Mutations in this pathway have devastating consequences. When such mutations happen in adults, they can lead to cancer. Mutations that occur in embryos can cause major developmental birth defects, including abnormally large brains. After birth, these developmental problems can cause intellectual disabilities, autism and epilepsy. Children with this kind of epilepsy often do not respond to currently available seizure medications. There are several outstanding questions that if answered could help efforts to develop treatments for children with brain growth disorders. Firstly, how do the developmental abnormalities happen? Do the abnormalities themselves cause epilepsy? And can drugs that target this pathway, and are already in clinical trials for cancer, control seizures? Now, Roy et al. have made mouse models of these human developmental brain disorders and used them to answer these questions. The mice were genetically engineered to have various mutations in the gene that encodes the catalytic subunit of the PI3K enzyme. The mutations were the same as those found in people with brain overgrowth disorders, and were activated only in the developing brain of the mice. These mutations caused enlarged brain size, fluid accumulation in the brain, brain malformations and epilepsy in developing mice – thus mimicking the human birth defects. The severity of these symptoms depended on the specific mutation and when the mutant genes were turned on during development. Next, Roy et al. studied these mice to see if the seizures could be treated using a drug, that has already been developed for brain cancer. This drug specifically targets and reduces the activity of PI3K. Adult mutant mice with brain malformations were treated for just one hour; this dramatically reduced their seizures. These experiments prove that seizures associated with this kind of brain overgrowth disorder are driven by ongoing abnormal PI3K activity and can be treated even when underlying brain abnormalities persist. Roy et al. suggest that drugs targeting PI3K might help treat seizures in children with these brain overgrowth disorders.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.12703.001
DOI:
10.7554/eLife.12703.002
DOI:
10.7554/eLife.12703.003
DOI:
10.7554/eLife.12703.004
DOI:
10.7554/eLife.12703.005
DOI:
10.7554/eLife.12703.006
DOI:
10.7554/eLife.12703.007
DOI:
10.7554/eLife.12703.008
DOI:
10.7554/eLife.12703.009
DOI:
10.7554/eLife.12703.010
DOI:
10.7554/eLife.12703.011
DOI:
10.7554/eLife.12703.012
DOI:
10.7554/eLife.12703.013
DOI:
10.7554/eLife.12703.014
DOI:
10.7554/eLife.12703.015
DOI:
10.7554/eLife.12703.016
DOI:
10.7554/eLife.12703.017
DOI:
10.7554/eLife.12703.018
DOI:
10.7554/eLife.12703.019
DOI:
10.7554/eLife.12703.020
DOI:
10.7554/eLife.12703.021
DOI:
10.7554/eLife.12703.022
DOI:
10.7554/eLife.12703.023
DOI:
10.7554/eLife.12703.024
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2015
detail.hit.zdb_id:
2687154-3
