Gene protects developing brain

Researchers have found a gene that may be responsible for an individual’s susceptibility to mental disease.

Scientists have known for the past five decades that the gene Heat Shock Factor 1 (Hsf1) is involved in keeping adult neural degenerative diseases at bay. Now, investigators have found that fetal mice without the gene expressed are more likely to develop a variety of brain development disorders — including epilepsy, cell death, and schizophrenia — after being exposed to stressors. Researchers interviewed said that while the findings have the potential to develop into therapies, their short-term implications are more uncertain.

“What we found is a gene that responds to the environment to protect the fetal brain,” said Kazue Hashimoto-Torii, professor of neuroscience at George Washington University and lead author of the paper. “This gene can reduce the risk of certain types of disorders.”

Hsf1 is triggered by stress and modifies how other genes are expressed. The multistage study first discovered that Hsf1 was activated after fetal mice were exposed to different environmental stressors, including alcohol, mercury and maternal seizures. The authors then examined that likelihood of developmental problems in prenatal mice that were exposed to the same stressors and found mice without the Hsf1 gene more often had developmental disorders. Finally, the researchers examined stem cells from adult humans with schizophrenia and found abnormal manifestations of the Hsf1 gene’s signaling process.

Pasko Rakic, a professor of neuroscience at the Yale School of Medicine and senior author of the paper, said further research is required in order confirm the study’s conclusion for human cells. Rakic also said that the study suggests that the certain period of stressed development could explain which disease develops, with the expression of Hsf1 co-occurring with the development of the part of the brain implicated in the disorder.

Rick Morimoto, a professor of biology at Northwestern University who was not involved in the research, said the study is novel because it took a developmental perspective on a gene previously explored in developed humans.

“What’s most exciting is that it’s linking together very different fields,” Morimoto said. “This is a beautiful basis science question.”

Morimoto added that such cellular and molecular investigations are conducive for developing treatments. The research can potentially lead to diagnostic approaches, which are key to early diagnosis of these disorders.

Ivor J. Benjamin, a professor of biochemistry at the University of Utah not involved in the study, said significant future research will be needed before the Hsf1 pathway could be manipulated for treatments.

Arthur Horwich, professor at the Yale School of Medicine who did not work on the study, said it is difficult to tell how Hsf1 should be manipulated developmentally to prevent disease, especially the process involved in artificially expressing the gene can be toxic.

“I am not sure how this translates easily into a sort of diagnostic setting,” he said.

Both Benjamin and Morimoto emphasized that the study reports a biological pattern of mice in utero, and that much work will be needed before the research can be applied to human diagnostics and treatment.

The paper will be published in the journal Neuron on May 7.

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