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Cancer drug could soon make therapy possible / Publication in the journal Nature

A gene mutation in microglial cells, the immune cells of the brain, can be the trigger for a severe neurodegenerative disease. This was demonstrated in mice by an international team of scientists co-led by Prof. Dr. Marco Prinz, Medical Director of the Institute of Neuropathology at the Medical Center - University of Freiburg. If the BRAF gene is already altered in early developmental stages of the immune cells well before birth, microglial cells proliferate excessively in adulthood, triggering inflammatory reactions in the brain and ultimately leading to the death of nerve cells. When the researchers fed the animals an inhibitor against the BRAF molecule, which is only altered in microglial cells, the brain damage and behavioral changes in the mice occurred much later and to a lesser extent. People with such a genetic alteration also develop a neurodegenerative disease in the course of their lives. The extent to which the new findings can be transferred to Alzheimer's, Parkinson's and other neurodegenerative diseases will be investigated in further studies. The study was published on August 30, 2017 in the renowned journal Nature.

The brains of patients with neurodegenerative diseases show a pronounced activation of microglial cells in addition to nerve cell loss. It was previously unclear whether this is the cause or consequence of the disease and whether this effect protects or damages the brain. "Our study is the first to prove that immune cells in the brain can trigger neurodegenerative diseases. At the same time, this opens up a new, very interesting therapeutic approach," says Prof. Prinz, who is also the spokesperson for the Collaborative Research Center/Transregio 167 "Neuromac" of the German Research Foundation.

For their study, the researchers introduced the modified BRAF gene into immature microglial cells before the mice were born. As a result, the animals developed the first signs of paralysis at four to five months of age, as can also occur in patients with neurodegenerative diseases. After nine months, the paralysis was very severe in more than half of the animals and there was a pronounced loss of nerve cells. However, if the animals were given a BRAF inhibitor early and regularly in their feed, only one in five animals showed more severe neurological impairments after nine months and the neurodegeneration in the brain was halted.

Cancer drug could stop disease

This gene mutation also leads to neurodegeneration in humans, as the researchers from Germany, the UK and the USA were able to demonstrate in five patients with the rare immune disease histiocytosis. As BRAF also plays a role in the development of aggressive tumors, clinically approved inhibitors have been available for a few years. The Freiburg researchers are pinning their hopes on these drugs. "In the best-case scenario, these cancer drugs could also be used in the future to treat certain neurodegenerative diseases with this mutation in microglial cells," said one of the study's leading authors Dr. Thomas Blank, head of a research group at the Institute of Neuropathology at the Medical Center - University of Freiburg, who investigated the mechanisms of neurodegeneration in the study together with medical student Marius Schwabenland.

Original title of the study: A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease

DOI: 10.1038/nature23672

Link to the study:www.nature.com/nature/journal/vaop/ncurrent/full/nature23672.html

Contact:
Prof. Dr. Marco Prinz
Medical Director
Institute of Neuropathology
Medical Center - University of Freiburg
Phone: 0761 270-51060
marco.prinz@uniklinik-freiburg.de