Could schizophrenia arise from a single defect?

February 16, 2005

Researchers have long puzzled over the apparently multiple causes of complex developmental disorders such as schizophrenia. Individuals seem to be predisposed to the disease by a tragic, mysterious combination of genetics, prenatal trauma, viral infection, and early experience. And its array of symptoms--including hallucinations, delusions, paranoia, and antisocial behavior--has defied simple explanation.

In experiments with rats, however, researchers led by led by Gerard J.M. Martens of the Nijmegen Center for Molecular Life Sciences (NCMLS) have demonstrated that such seemingly diverse combinations of symptoms can arise from a subtle imbalance in the activity of a single gene whose protein plays a key role in neural development.

The researchers studied the genetic differences between rats bred to be either resistant or susceptible to the drug apomorphine. A long history of studies has revealed that apomorphine-susceptible rats show many behavioral and biochemical differences from normal rats. What's more, the tendency to develop these differences depends on their exposure to stress in early life.

To search for genetic differences between the two types of rats, the researchers used microarrays, or so-called "gene chips," to analyze the activity of thousands of genes in the rats' brains. To their surprise, they discovered only a single genetic difference between the two groups of rats. The levels of activity of a gene called Aph-1b tended to be lower in the susceptible rats than in the non-susceptible rats. Importantly, this gene produces a protein that is a component of an enzyme called g-secretase, which plays a role in regulating many processes in the developing brain. The researchers found that, as a result of this lower level of Aph-1b protein, g-secretase showed reduced activity in the brains of the susceptible rats.

What's more, when the researchers tested various behaviors of "sublines" of rats with different levels of Aph-1b, they found that their behaviors correlated with those levels--termed a "gene dosage effect."

"Thus, a subtle imbalance in the expression of a single gene product that is involved in a wide variety of developmental signaling pathways may well constitute the molecular basis of a complex phenotype that is generally believed to have a multifactorial background," concluded the scientists.
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The researchers include Marcel W. Coolen, Karen M.J. Van Loo, Nick N.H.M. Van Bakel, and Gerard J.M. Martens of the Nijmegen Center for Molecular Life Sciences (NCMLS) and Institute for Neuroscience at Radboud University Nijmegen; David J. Pulford of Target Discovery at Organon Laboratories Limited; Lutgarde Serneels and Bart De Strooper of the Flanders Interuniversity Institute for Biotechnology (VIB) and Center for Human Genetics at Katholieke Universiteit Leuven; and Bart A. Ellenbroek and Alexander R. Cools of Nijmegen Institute for Neurosciences (NIN) at Radboud University Nijmegen. This work received support from the Netherlands Organization for Scientific Research (NWO). B.D.S. was supported by a Pioneer award from the Alzheimer's Association, grant IUAP P5/9, and EU contract LSHM-CT-2003-503330 (APOPIS).

Marcel W. Coolen, Karen M.J. Van Loo, Nick N.H.M. Van Bakel, David J. Pulford, Lutgarde Serneels, Bart De Strooper, Bart A. Ellenbroek, Alexander R. Cools, and Gerard J.M. Martens: "Gene dosage effect on -secretase component Aph-1b in a rat model for neurodevelopmental disorders"

Publishing in Neuron, Volume 45, Number 4, February 17, 2005, pages 495-503.

Cell Press

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