Nervous disorders investigated using reprogrammed stem cells

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Researchers in Bonn have reprogrammed skin cells into nerve cells to investigate a rare neurological disease. Source: Brüstle

08.12.2011  - 

The Bonn-based scientist Oliver Brüstle is again making the headlines following the end of the European legal dispute over stem cell patents. Brüstle’s team at the Forschungszentrum Life & Brain have been successful in their laboratory studies of a rare neurodegenerative disease. The researchers used reprogrammed somatic cells from patients suffering from Machado-Joseph disease, a hereditary movement disorder. Aided by artificially induced pluripotent stem (iPS) cells, the researchers were able to extract functioning nerve cells for examination in the lab. The researchers have reported on their findings in the trade journal Nature (2011, online prepublication).

Neurodegenerative diseases are difficult to investigate in the laboratory, and animal models for reproducing complex diseases such as Alzheimer's or multiple sclerosis are rare. Likewise, using human tissue poses its own major challenges. Today, however, brain researchers are placing high hopes in stem cells. In particular, by applying the technique of reprogramming, it is possible to derive artificial stem cells (iPS cells) from the somatic cells of patients; by using other molecular tricks, the researchers can then force these to develop into a particular tissue.

A team of researchers led by neuropathologist Oliver Brüstle in Bonn has now exploited this approach in their investigations of Machado-Joseph disease. Brüstle is a stem cell research pioneer, but has also been making the headlines outside of the laboratory of late: The environmental organisation Greenpeace succeeded in annulling Brüstle’s stem cell patents in a lawsuit up before the European Court of Justice (ECJ). In October 2011, the ECJ ruled that any procedure that follows from the destruction of an embryo is excluded from patentability (more...). This was in line with a request from Advocate General Yves Bot, and in opposition to the demands of many researchers.

Machado-Joseph disease – now in the sights of the researchers in Bonn – is a motor coordination disorder, originally described in Portuguese-born residents of the Azores, and today the most common dominantly inherited cerebellar ataxia (a disorder of the nervous system which affects balance and coordination) in Germany. The majority of patients develop gait disorders and a range of other neurological symptoms between the 20th and 40th year. The cause of the disorder is a repetitive gene sequence in the gene known as ataxin-3, which leads to the clumping of the corresponding protein, eventually damaging the nerve cells in the brain.

Directly researching affected cells

To date, it has remained unclear why the disease affects only nerve cells, and exactly how abnormal protein aggregation is triggered. To study the disease process at the molecular level, the scientists in Bonn first presented so-called induced pluripotent stem cells (iPS cells) taken from patient skin samples. This concerns cells that have been reset into a very early, undifferentiated stage. Once extracted, these ‘all rounders’ can be reproduced almost indefinitely, and have the potential to develop into all types of cells in the body. In the next step, Brüstle’s team transformed the iPS cells into brain stem cells, from which the scientists could develop any kind of nerve cells for their studies. The special characteristic: Because the nerve cells originate from the patient themselves, they carry the same genetic characteristics, and can thus serve as a cellular model for the disease. “This method allows us to study the disease in the genuinely affected cells, to which we would not otherwise have access. It’s almost as if we’ve put the patient's brain into the Petri dish,” says lead author of the study, Philip Koch.

Electrical stimuli

When Koch electrically stimulated the artificially created neurons, it emerged that the formation of protein aggregates is directly related to the electrical activity of the nerve cells. A key role seems to be played by the enzyme calpain, which is activated by the increased calcium content of stimulated nerve cells. “This newly identified mechanism explains why the disease affects only nerve cells,” says Brüstle. “The study illustrates the potential that this particular type of stem cell has for neurological disease research,” says Thomas Klockgether, Clinical Director of the German Center for Neurodegenerative Diseases (DZNE), and Director of the Neurology Clinic at Bonn University, whose team is closely involved in the study with Brüstle’s team. In a next step, Brüstle and his colleagues at Life & Brain are planning to use reprogrammed nerve cells for the development of therapeutics for the treatment of neurological diseases.

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