Cracking the brain’s genetic code pg. 2
It’s probably impossible, given the difference in the brains of a rodent and a human, to model it perfectly, but I think useful information will come. It will be one of the ways the field progresses.
Coyle: I think in our field, the best example has been the work in Alzheimer’s disease. Mice don’t develop the pathology of Alzheimer’s disease because the gene that encodes the protein that creates amyloid deposits in human beings has a different amino acid sequence in the mouse, and so amyloid deposits are not formed naturally in rodents. Scientists have created an animal model for Alzheimer’s disease by inserting into the mouse genome the mutation in the human gene that has been linked to the inherited form of Alzheimer’s disease. A similar approach has been used with another gene, the mutant human presenilin gene, which increases the risk for Alzheimer’s disease and acts on the amyloid protein.
And so we now have mice that develop the pathology of Alzheimer’s disease. Major drug companies are developing drugs that will interfere with the generation of the amyloid or enhance its clearance. So, while these mice may not be behaviorally perfect models of Alzheimer’s disease, they certainly are powerful tools for teasing apart the pathologic pathway and providing drug targets.
How do you think our increased understanding of the genetics of brain disorders will ultimately improve drug development?
Scolnick: Through the emerging risk genes. But we’re only really starting to identify them because they required the human genome sequence being there in order to really make progress in the field. So it’s much too early for that to pay off with practical new therapeutics.
Coyle: I would agree. It’s a lot more complicated than disorders that follow classical Mendelian genetics. Autism, schizophrenia, the mood disorders involve, or likely involve, what is known as complex genetics in which there will be multiple genes of small effects that in combination result in the observed disease, and so that presents real challenges.
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