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Gene linked to myelin repair in the brain

17 December 2004

Scientists have identified a genetic repair process in the brain that can re-coat nerves with myelin - fatty 'insulation' - that is stripped away in multiple sclerosis.

In a study published in the December 17 issue of the journal Science, scientists from the Centre for Brain Repair and the School of Veterinary Medicine at the University of Cambridge and the Dana-Farber Institute at Harvard University, report that the gene Olig 1, thought to aid the development of certain brain cells, is essential for the myelin-repairing process in adults with Central Nervous System (CNS) diseases like Multiple Sclerosis (MS).

Affecting about two and half million people worldwide, MS is an inflammatory disease of the CNS and one of the most common causes of neurological disability in young adults. Symptoms of the disease range from fatigue and numbness to difficulties with memory, speech and movement and alternately worsen and improve in an unpredictable 'relapsing/remitting' pattern. During remissions, randomly damaged nerves in the brain and spinal cord become recovered with myelin, a fatty substance forming the insulating sheath around long, threadlike nerve cells that transmit signals in the form of electrical impulses.

Working with tissue from rodents and humans, the researchers determined that the Olig 1 gene jump-starts a process that can restore, at least temporarily, the myelin coating of nerves damaged in MS.

The two teams headed by Drs Charles Stiles and David Rowitch in Boston and Dr Robin Franklin in Cambridge, investigated the role of the Olig 1 gene. When Olig1 and its close relative Olig2 were initially identified, it appeared that Olig2 was required for the fetal development of oligodendrocytes (cells that provide the myelin to wrap nerves in the CNS) while the role of the Olig 1 gene was not determined.

In order to identify the role of the Olig 1 gene, the two teams used antibodies to highlight the location of the proteins encoded by Olig 1 and 2 in brain cells from embryonic and adult mice. While in embryonic cells both proteins were located in the nucleus, as anticipated since their role is to regulate expression of other genes that produce the myelinating cells, in adult cells the Olig 1 protein had migrated to the cytoplasm outside the nucleus, where there are no genes to regulate.

Looking for the location of Olig 1 in adult rodents with a demyelinating injury, however, the researchers found that Olig 1 would appear in the nucleus. That is, following an injury the brain cells had in effect reverted to a fetal state in which Olig 1 could trigger the formation of new oligodendrocytes.

Furthermore, when the researchers induced demyelinating lesions in Olig 1 'knockout mice' that could not produce the Olig 1 protein, they found that although brain developed normally it could not repair the demyelinating lesions.

Together with Dr Cedric Raine from the Albert Einstein College of Medicine in New York, the scientists used post mortem brain tissue from MS patients to pinpoint the location of Olig 1 in the human samples. In the healthy areas of the brain, the Olig1 gene appeared inactive while in damaged regions it was active, and possibly contributing to the formation of new oligodendrocytes.

"This suggests that the Olig 1's function has been shaped by evolution to repair the brain in areas where the insulating layer of myelin has been depleted through disease,"

said Dr Franklin, lead investigator of the Cambridge Centre for Brain Repair team.

While the cycle of damage and repair can go on for many years in MS patients, eventually the system wears down, and in most people the disease progresses with fewer remissions.

"Perhaps the signal that calls Olig 1 into service becomes weaker,"

said Dr Stiles lead investigator of the Dana-Faber Institute team.

"Although this finding will not yield direct results in terms of finding treatment for MS we are confident that it gives new insight and direction for research."

The researchers conclude that although MS may not be completely preventable, there is hope that therapeutic approaches, focusing on the repair process will be available in the future.

Notes for Editors:

1. Cambridge Centre for Brain Repair: The ultimate aim of work in the Centre is to understand, and eventually to alleviate and repair damage to the brain and spinal cord which results from injury or neurodegenerative disease. The Centre was formed to bring Cambridge scientists working across the many fields of modern neuroscience together in cross-disciplinary research efforts directed at the problems associated with preventing or repairing the effects of brain damage. The approach being taken is both a long term one of trying to understand the underlying disease mechanisms, and a more immediate examination of strategies that might have potential for clinical application. Towards this end a major goal of the Centre is to provide a forum for interactions between investigators in the clinical and basic neurosciences.

2. Dr Robin Franklin is a researcher at the Centre for Brain Repair and the School of Veterinary Medicine at the University of Cambridge. The goal of his lab is to devise new ways of repairing damage to the CNS through an understanding of the mechanisms of regenerative processes. A particular focus is on the regeneration of myelin sheaths damaged in diseases like multiple sclerosis and of axons damaged in traumatic injury.

3. The Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

4. Drs Charles Stiles and David Rowitch are investigators and long-term collaborators at the Dana-Farber Cancer Institute. Their two laboratories work on transcription factors such as Olig1 and Olig2 that direct formation of the normal brain from neural stem cells during development. Disruption of genes that direct brain development may be relevant to cancers of the brain and a wide variety of other neurological diseases such as MS.

5. The National Multiple Sclerosis Society in the U.S. has created a new type of research grant aimed at attracting scientists from outside the MS field to provide new ideas in order to enable research.

6. Some of the human tissue used in the study was supplied by the UK MS Society tissue bank.

For more information, contact:

• 1. Corina Hadjiodysseos, Press and Publications Office, University of Cambridge Tel: 01223 332300, email: ch250@admin.cam.ac.uk

  2. Dr Robin Franklin, Centre for Brain Repair and Centre for Veterinary Sciences, University of Cambridge Tel: 01223 337642, email: rjf1000@cam.ac.uk

  3. Dr. Charles Stiles, Dana-Farber Cancer Institute Tel: + 1- 617 632-3512 Email: charles-stiles@dfci.harvard.edu