The group of researchers led by Prof. Orna Ellroy-Stein from the Faculty of Life Sciences published today in the journal BRAIN that they were able to use genetic engineering to develop mice suffering from the atrophy of the white matter of the brain (VWM), which will be able to help in the search for cures for this serious disease and for other neurodegenerative diseases in humans such as Multiple Sclerosis
Cerebral white matter loss is an incurable neurodegenerative genetic disease. The classic manifestation of the disease is characterized by the appearance of neurological signs (motor and cognitive) in childhood, which gradually worsen until complete paralysis ends in death after several years. Accelerated deterioration of clinical signs occurs after high fever, head injury, or sudden fear.
The disease is caused by point mutations in the gene that codes for the enzyme (eIF2B) whose genetic code is highly conserved in evolution, and which has an essential role in the synthesis of the entire repertoire of proteins, in all types of cells. The mutations, which can be of varying degrees of severity, cause a decrease in the enzymatic activity but not its elimination altogether. This enzyme is known for its importance in controlling the translation of RNA into protein.
To the researchers' surprise, although the function of this enzyme is essential in all body cells, mutations in it mainly cause problems in the white matter of the brain, for an unknown reason. After the gene responsible for the disease was identified, the race began to develop a strain of mice carrying a mutation in this gene, to enable intensive research that cannot be realized in humans. The research will lead to the identification of early signs of the disease, to the identification of environmental factors that accelerate the onset and deterioration of symptoms, and to the understanding of the molecular mechanisms that will lead to the development of drugs.
The research group led by Professor Orna Ellroy-Stein from the Faculty of Life Sciences at Tel Aviv University succeeded in developing model mice for the disease and published the first insights into the white matter anomaly as a result of the mutation, in the BRAIN newspaper. Students Michal Geva, Yuval Kabili, Liraz Marom, Nina Mindrol, Dalia Panhassi, and Gali Raini participated in the study in collaboration with Dr. Yaniv Assaf from the Department of Neurobiology.
The researchers used genetic engineering methods to change the mouse gene that codes for the catalytic subunit of the enzyme, and insert a specific mutation into it that caused a decrease of about 20 percent in its activity. From a single cell that contained the desired mutation, the researchers created a new strain of mice. Continuous monitoring of tiny changes in the mice's brain by magnetic resonance imaging (MRI), it was found that the mutation causes the delay in the development of specific areas of the brain and also the start of neurodegeneration processes at an early age. It was also found that the mutant mice were unable to repair targeted damage in the white matter while the control mice repaired the damage after several weeks.
The normality and integrity of the white matter in the brain depends on careful control of the production process of proteins that are part of the building blocks of myelin or are essential to the process of its creation. Myelin is the insulating substance that wraps the nerve cell extensions and it allows the efficient transmission of the nerve signal. Its defective structure or its disintegration causes problems in the passage of electrical signals and neurological symptoms according to the function of the damaged nerve cells. So far no genes have been identified whose translation control is critical for the formation and maintenance of myelin integrity.
There are many diseases of the white matter in the brain, the best known of which is multiple sclerosis. The strain of mice developed at Tel Aviv University will enable the understanding of the control processes essential to the formation of the white matter at a young age and maintaining its integrity in response to damages that occur at various times throughout life. This important information will be of great use for the development of drugs that will be valuable for a variety of neurodegenerative diseases.
