Dangers in DNA

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McGill Reporter
February 21, 2002 - Volume 34 Number 11
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Dangers in DNA

Montreal Neurological Institute neurologist Eric Shoubridge recently received a major funding boost from one of the world's choosiest foundations.

Photo Professor Eric Shoubridge
PHOTO: Normand Blouin

Shoubridge was one of 43 scientists from Canada or Latin America to receive an International Research Scholar Award from the Howard Hughes Medical Research Institute (HHMI). The prize comes with a $350,000 grant over five years.

The HHMI awards tend to go to some of the best medical scientists in the world and many a Nobel Prize winner has an HHMI grant on his resumé. Biochemistry professor Nahum Sonenberg, a researcher looking at cancer and obesity, also earned HHMI funding this year.

"This award will allow us to look much more in-depth at the problems we have been tackling for several years now," says Shoubridge. "We will be able to hire a few more people. I think it will allow us to get to the answer faster."

Shoubridge is trying to answer a number of questions about the genetic key to mitochrondrial diseases.

Mitochondria are the cellular engines that produce the energy for our bodies. Defects in mitochondria are the cause of 40 known types of diseases, which primarily affect brain and muscle function.

Some of these disorders are particularly dangerous or debilitating and the symptoms associated with them can include neurodegeneration, stroke-like episodes, seizures, muscle weakness, deafness and blindness. Mitochondrial diseases are also very difficult to diagnose.

"We are interested in how mutations that cause those diseases are transmitted from one generation to the next," says Shoubridge. "Mitochondrial DNA is transmitted to us from our mothers, but mothers can transmit a variable amount of mutated genes to their offspring. If they transmit a lot of them, it can cause disease."

Shoubridge and his graduate students developed an animal model to determine how this genetic transfer occurs.

"What we found is that this is a [seemingly] completely random process; but in some tissues of the animals, it's not so random. Some tissues are selecting for one kind of mitochondrial DNA and other tissues are selecting for other kinds. We have been involved in figuring out what nuclear genes control that behaviour." Nuclear genes refer to DNA contained in the nucleus of cells.

"We think these genes are involved in the coding of proteins which are, in turn, responsible for the organization of mitochondrial DNA. But we don't have any idea what these proteins are, at least not in humans."

Thus, a part of the HHMI grant is dedicated to looking at fundamental aspects of the organization of mitochondrial DNA in human cells.

"We hope that understanding this organization will give us some insight on how mitochondrial diseases progress over time. We know that these disorders get worse as the patients age, and that reflects an increase in the proportion of mitochondrial DNA that are carrying a particular mutation. For example, maybe 10% of the mitochondrial DNA that you inherited from your mother might have contained a particular mutation, but after you're born, that proportion can increase.

"We think it may be because of the way this DNA replicates in the cell; there may also be defective genes among the nuclear genes that control mitochondrial DNA. But we don't really know yet why the ratio of good guys to bad guys changes. We have to investigate further using our animal model."

One theory is that cells may be forced to replicate mutated genes as well as normal ones.

"We think that when the cells have a defective energy producing system, they try to recover from that. Cells have a system for regulating the number of mitochondria, according to how much energy they need, and whether or not there is a deficit. So while they try to make up the deficit by producing more mitochondria, they may, as an accidental by-product, amplify the mutant mitochondrial DNA."

An important next step, if this theory is proven correct, will be to map the signalling pathway by which the cell tells the genes in the nucleus to produce more mitochondria.

Shoubridge's lab works on fundamental principles which underlie many or most incidences of mitochondrial diseases. His team is also working on parallel studies that examine particular diseases in this family of disorders.

In 1998, one of these studies produced a breakthrough in our understanding of Leigh Syndrome (LS), a disease characterized by brain lesions. Shoubridge's lab identified the mutant gene, called SURF 1. The lab also fingered the genetic culprit responsible in hypertrophic cardiomyopathy, a disease that makes the hearts of newborn babies swell and eventually give out, in the first months or years of life.

Shoubridge says the best application of the discovery is in the prevention of the disease at the prenatal stage, because therapies for sick patients are usually ineffective, and the diseases are often fatal. Parents who both carry the defective gene have a one in four chance of producing offspring with the disease. But today they can reduce the odds to zero through genetic counselling.

"Parents who have already had a child who suffered from this disorder can avoid facing that again. They can now get prenatal diagnoses or, if they are pursuing in vitro fertilization, they can choose embryos that are not carrying the genetic defect. The real reason for identifying the root causes of these disorders is to give parents the chance to avoid them altogether."

In March, Shoubridge's team will publish a paper mapping genes that are involved in the organization of mitochondria by DNA in the nucleus.

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