Gene defect causes dementia symptoms

New disease discovered: Gene defect causes dementia-like symptoms

06/14/2012

A newly discovered gene defect causes typical symptoms of dementia. The research team headed by Professor Thomas Dierks from the University of Bielefeld has discovered an enzyme genetic disease that causes a progressive loss of mental abilities in mice. The proven in mice sub-form of the so-called Mucopolysaccharidose syndrome cause significant limitations of cognitive skills, such as forgetfulness, learning and coordination difficulties, the researchers report in the US journal "Proceedings of the National Academy of Sciences" (PNAS). After her discoverer, the disease was named "Dierks'sche illness" (also MPS III). The biochemist Dierks and his team presented not only the discovered gene defect but also a therapy concept in which the defective enzyme is replaced by an artificially produced one.

Gene defect causes previously unknown disease
The international team of researchers led by biochemist Prof. Thomas Dierks demonstrated in his research that "damage to the enzyme arylsulfatase G (ARSG) in mice triggers the disease MPS III," reports the University of Bielefeld in a recent press release. In general, enzymes take over the construction and splitting of nutrients and messengers in the human organism. If defective enzymes are produced as a result of an inherited disorder, they can no longer adequately exercise their control function. Affected people "become ill, for example because substances accumulate in their bodies that can no longer be split," according to the Bielefeld University. The corresponding genetically caused metabolic diseases are summarized under the term "Lysosomal storage diseases". Almost 50 of these diseases are currently known. One of them is the "Dierks disease" now found in mice.

Enzyme damage as a result of the gene defect
The gene defect discovered by Prof. Dierks and colleagues causes damage to the enzyme arylsulfatase G, which normally has a significant share in the breakdown of the carbohydrate heparan sulfate. In healthy mice, heparan sulfate molecules that are no longer needed within the cells are "broken down into their smallest building blocks, from which later new molecules are assembled," reports the University of Bielefeld. Due to the failure of the ARSG enzyme, the entire recycling plant breaks down in the cells. The molecular chains remain and accumulate in the cells in the lysosome. This finally stops working and then "other substances, such as proteins and fats, are no longer degraded," according to the University. As a result, according to the researchers, the lysosome "continues to expand until it damages the entire cell and eventually disappears." Professor Dierks describes the process of the disease as follows: "If the enzyme is not functioning properly, the waste will simply remain, and the cell is finally stuffed with garbage until it is destroyed "."

Behavioral tests show the cognitive impairment
The effects of the gene defect or the damage of the ARSG enzyme in mice, the researchers determined using various tests. Since ARSG serves to break down the heparan sulfate molecules in the nerve cells of the cerebellum, it was suspected that a disruption of the process could also be associated with cognitive impairment. This was verified by Dierks and colleagues on the basis of various behavioral tests, for example, in which the response of the mice when they came to an open field was observed. In contrast to their healthy counterparts, the animals with the gene defect were rather on the safe side and did not dare to go exploring, the scientists report. Another test was the water labyrinth, where the mice were trained to "float in a pool filled with milky liquid, finding a platform hidden beneath the surface," reports the University of Bielefeld. From the age of twelve months, the animals with the gene defect could no longer remember the previously learned position of the platform and needed much longer to discover them. At a younger age, the mice had found the platform as effortlessly as their healthy counterparts.

Nerve cells destroyed in the cerebellum
From the age of twelve months, the mice with ARSG defect show clear cognitive disorders, the scientists report in their article in the journal "PNAS" The reason for this lies in the impairment of the nerve cells in the cerebellum of the animals. Tissue samples from the cerebellum of mice showed that "the accumulation of heparan sulphate causes the Purkinje cells in the cerebellum to die and, accompanied by inflammation, to be replaced by new cells," according to the Bielefeld University. Professor Dierks further explained that these glial replacement cells only have a supporting function and do not develop new nerve connections.

Approaches to the therapy of the newly discovered disease
Dierks and colleagues see in their research results a significant success, as based on the detected enzyme damage, a therapy for hereditary disease can develop. For example, the researchers artificially produced fully functional ARSG enzymes "in a biotechnological process using genetically modified cell cultures" in order to subsequently use them for the treatment of the mice. If the solution containing the enzyme is regularly injected into the diseased mice, "the damage to the organs should be stopped," according to the Bielefeld University. The findings are also of importance to humans, since "the biochemical processes that are associated with such lysosomal storage diseases are in principle the same in all mammals," reports Professor Dierks. "We are almost certain that the defect also occurs in humans," said the Bielefeld biochemist. In humans, however, the corresponding diseases usually have a more serious effect due to the older age, Dierks continues. (Fp)

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