Heredity more important than previously believed

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Over the past 20 years, Parkinson's has gone from being regarded as entirely caused by environmental factors to a disease with a clear genetic links. But researchers have not yet identified the balance between heredity and environment.

The news came as a bombshell to the research community when in 1996 American scientists were able to demonstrate that a mutation in a specific gene region caused a dominant inheritance of Parkinson's in an Italian family. The next year, the same researchers could show that this related to the gene for the protein alpha-synuclein, which is abundant in the protein accumulations known as Lewy bodies. These had already been found in the cells of deceased Parkinson's patients in the early 1900s.

Bild på Lars Olson."Alpha-synuclein is a very important protein in this context, although we do not know yet what it does. Besides mutations, it's enough for someone just to have multiple copies of the normal gene to become ill with Parkinson's," says Lars Olson, professor at Karolinska Institutet's Department of Neuroscience.

In the 15 plus years that have passed since 1996, research on the genetics behind Parkinson's has made tremendous progress. Now scientists are aware of a further 15 gene regions that are directly linked to the disease or to an increased risk of being affected. For some regions, the exact gene has been identified, while for others it has not yet been found.

Today, about one in ten of all Parkinson's cases can be explained by a mutation in a single gene. The two most common mutations are those in a gene called LRRK2 and in the gene for alpha-synuclein.

But in the majority of Parkinson's cases, the disease has developed due to mutations in several genes acting as risk factors in certain combinations or together with an inopportune environment for that particular gene combination. Just how great a role genetics plays is still unclear (see separate article in our Parkinson's theme).

However, gene mutations need not only entail a greater risk. They can also act as a shield. Andrea Carmine Belin, a docent at Karolinska Institutet's Department of Neuroscience, talks about a gene she has investigated in which a particular mutation impairs the action of an enzyme that detoxifies substances in the body such as insecticides. This mutation is more common in Parkinson's patients. But at the same time, there is another mutation in the same gene that instead enhances the effect of the enzyme, and this is more common in those who do not have the disease. In other words, the mutation acts as a shield.

Andrea Carmine Belin says that since the genetic causalities are quite complex, it will not be possible to find a single cure, but multiple lines of treatment will be necessary. In fact, researchers now believe that what we call Parkinson's disease is not even one and the same disease.

"It is rather several different subtypes of disease that have a similar array of symptoms," says Lars Olson.

Despite the total focus of research and treatment on dopamine, it does not either appear as if Parkinson's actually affects the dopamine cells specifically or in a particularly aggressive manner compared to other cells in the brain.

"Not one of the genes that have so far been linked to Parkinson's has any specific relationship to dopamine cells. Not one," says Lars Olson.

That it is nevertheless the degenerating dopamine cells and lack of dopamine which cause the classic symptoms that are virtually always those leading to a diagnosis could be due to the dopamine cells being particularly sensitive. But this is as yet unknown.

New genetic knowledge about Parkinson's will hopefully lead to new treatments in the future.

"I think there will soon come a wave of new treatments based on the new knowledge from genetics," says Lars Olson.

However, he says that it may still be a long way to the big goal of finding a cure and that it is difficult to assess where research is in relation to the ultimate goal.

"We are now in the middle of the second lap, but we don't know how many laps there are."

Text: Fredrik Hedlund. Published in Medicinsk Vetenskap 2/2013