Genetic defect causes dementia symptoms

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New disease discovered: gene defect causes dementia-like symptoms

A newly discovered gene defect causes typical symptoms of dementia. The research team led by Professor Dr. Thomas Dierks from the University of Bielefeld has discovered an enzyme hereditary disease that triggers a progressive loss of mental abilities in mice. The subform of the so-called mucopolysaccharidose syndrome, which has been detected in mice, causes considerable restrictions in cognitive abilities, such as forgetfulness, learning and coordination difficulties, the researchers report in the American journal "Proceedings of the National Academy of Sciences" (PNAS). The disease was named "Dierks disease" after its discoverer (also MPS IIIE). The biochemist Dierks and his team not only presented the discovered genetic 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 was able to prove in his research that "damage to the enzyme arylsulfatase G (ARSG) in mice triggers the disease MPS IIIE," reports Bielefeld University in one current press release. In general, enzymes take over the building and splitting of nutrients and messengers in the human organism. If defective enzymes are produced due to an inherited disorder, they can no longer adequately perform their control function. Affected people become “sick, for example because substances accumulate in their bodies that can no longer be split,” according to the Bielefeld University. The corresponding genetically determined metabolic diseases are summarized under the term "lysosomal storage diseases". Almost 50 of these diseases are currently known. One of them is the “Dierks’s disease” that has now been found in mice.

Enzyme damage due to 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 required are "broken down into their smallest building blocks from which new molecules are later assembled," reports Bielefeld University. Due to the failure of the ARSG enzyme, the entire recycling plant in the cells collapses. 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 broken down," the university said. As a result, according to the researchers, the lysosome "continues to expand until it damages the entire cell and eventually causes it to perish." Professor Dierks describes the process of the disease as follows: "If the enzyme does not work properly, the waste simply stays there, and the cell is finally filled with garbage until it is destroyed. "

Behavioral tests show the cognitive impairments The researchers used various tests to determine the effects of the gene defect or the damage to the ARSG enzyme in mice. Since ARSG serves to break down the heparan sulfate molecules in the cerebellum nerve cells, it was suspected that a disruption of the process could also be associated with cognitive impairments. Dierks and colleagues checked this using various behavioral tests, such as observing the response of the mice when they came into an open field. In contrast to their healthy counterparts, the animals with the genetic defect stayed on the safe side and did not dare to explore, the scientists report. Another test was the water labyrinth, in which the mice were trained to "find a platform hidden under the surface in a pool filled with milky liquid," reports Bielefeld University. From the age of twelve months, the animals with the gene defect could no longer remember the previously learned position of the platform and had to discover it much longer. At a younger age, the mice had found the platform as easily as their healthy counterparts.

Nerve cells destroyed in the cerebellum From the age of twelve months, the mice with an 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 the mice had shown that "due to the accumulation of heparan sulfate, the Purkinje cells in the cerebellum die and, accompanied by inflammation, are replaced by new cells," said the Bielefeld University. Professor Dierks further explained that these glia cells formed for replacement only have a supporting function and do not develop any new nerve connections.

Approaches to Therapy for the Newly Discovered Disease Dierks and colleagues see their research results as a major success, since therapy for the hereditary disease can be developed on the basis of the enzyme damage discovered. For example, the researchers artificially produced fully functional ARSG enzymes "in a biotechnological process with the help of genetically modified cell cultures" in order to then use them to treat the mice. If the solution with the enzyme is regularly injected into the diseased mice, "the damage to the organs should be stopped," said the Bielefeld University. The findings are also important for humans because "the biochemical processes associated with such lysosomal storage diseases are basically the same in all mammals," reports Professor Dierks. "We are almost certain that the defect will also occur in humans," emphasized the Bielefeld biochemist. In humans, however, the corresponding diseases usually have an even more serious impact due to their older age, Dierks continues. (fp)

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