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MS study offers theory for why repair of brain's wiring fails
Date:7/1/2009

the repair process the recruitment of oligodendrocyte precursors to the site of injury, the maturation of those cells into functional oligodendrocytes, and the formation of a new myelin sheath -- they measured the activity of 1,040 genes. All of the genes they studied encode transcription factors, which regulate the activity of other genes. Their experiments showed that 50 transcription factors are working during key steps in myelin repair.

The team then honed in on a gene called Tcf4, because its expression was strong in damaged areas where repair attempts were under way.

Tcf4 is involved in a cascade of biochemical events known as the Wnt (pronounced "wint") pathway, whose importance has been well recognized in normal development of many tissues, including the brain. Until now, however, Wnt had not been linked to myelin production or repair.

"This is the first evidence implicating the Wnt pathway in multiple sclerosis," says lead author Stephen P.J. Fancy, PhD, a postdoctoral fellow in the Rowitch lab. "We consider this an exciting development in our efforts to understand why the repair process often fails in the disease."

To glean further evidence about Wnt's role, the researchers hyperactivated the Wnt pathway in the oligodendrocytes of mice, which caused a profound delay in repair. Further analysis suggested that the Wnt pathway activation was creating a roadblock that prolonged oligodendrocyte precursor development.

"While the animals eventually showed repair, it was delayed compared to normal mice," says Fancy. The researchers also tested human tissue for the presence of Tcf4, and found the protein in areas damaged by MS but not in healthy white matter. Further, the researchers examined available data from another study and found that many signaling molecules of the Wnt pathway are overactive in lesions of patients with MS.

"This is an important step that we hope will lead to targeted therapies involving
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Contact: Jennifer OBrien
jobrien@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
Source:Eurekalert

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