New route to therapy for Rett syndrome?

February 01, 2006

While current treatments for Rett syndrome aim only at alleviating symptoms--including drugs to control seizures or aid motor coordination or breathing--a new study by Rudolf Jaenisch and colleagues raises the possibility of therapies targeting the root cause of the disease. They reported their discoveries in an article in the February 2, 2006, issue of Neuron.

Rett syndrome is the most common form of mental retardation in girls, affecting about one in 10,000. The X-linked disorder is particularly devastating, because while children with the disease are normal as infants, when they become toddlers they suffer a dramatic decline in physical and mental abilities. They experience language and growth retardation, breathing problems, seizures, motor dysfunction, hand-wringing, and social impairment.

The primary cause of Rett syndrome is a mutation in the gene for MECP2, or "methyl-CpG binding protein 2." In their study, Jaenisch and his colleagues explored how this mutation might affect the activity of another gene, called Bdnf. This gene is known to produce the "neurotrophic factor" BDNF that is essential for neuronal survival and the adaptability, or "plasticity," of connections among neurons. Bdnf had been known to be a target of control by MeCP2, but researchers did not know whether it played a significant role in the disease pathology.

In their studies of mice lacking the Mecp2 gene, Jaenisch and his colleagues found that the animals showed lower levels of BDNF. They also found that knocking out BDNF in normal mice produced some of the same Rett syndrome-like symptoms as mice lacking Mecp2. Knocking out both genes in the mice seemed to produce some additive effects, they found. Such mice died earlier than mice lacking only Mecp2 and showed more lethargy.

A key discovery came, however, when the researchers produced mice that lacked Mecp2 but had higher levels of BDNF. Such mice showed an increased lifespan compared to Mepc2-deficient mice, enhanced brain activity, increased locomotor activity, and some increase in brain weight.

The researchers concluded that these findings "demonstrate a functional interaction between these two genes." They theorized, however, that the interaction was indirect: "Given that BDNF expression depends on neuronal activity, we favor the hypothesis that Mecp2 deficiency reduces neuronal activity, thereby indirectly causing a decreased BDNF protein level," they wrote.

The latest findings of BDNF involvement in Rett syndrome add to the diseases linked to abnormal BDNF expression--which is also found in Huntington's disease, schizophrenia, and depression--noted the researchers.

"Our findings provide in vivo evidence of a functional interaction between Mecp2 and Bdnf," concluded the researchers. "Furthermore, our results indicate that manipulating the BDNF level or the BDNF signaling pathways may present therapeutic opportunities for [Rett syndrome] patients."

They also wrote that "Although BDNF is only one of many genes regulated by MeCP2, it is the first one shown to modulate disease progression of Mecp2 mutant mice."
The researchers include Qiang Chang of the Whitehead Institute for Biomedical Research in Cambridge, MA; Rudolf Jaenisch of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, MA; Gargi Khare of the Massachusetts Institute of Technology in Cambridge, MA; Vardhan Dani and Sacha Nelson of Brandeis University in Waltham, MA. Q.C. was supported by a postdoctoral fellowship from the Rett Syndrome Research Foundation. S.N was supported by a McKnight Foundation grant. R.J. was supported by a G.E.A.R. award from the Rett Syndrome Research Foundation and by a grant from the NCI (RO1 CA087869).

Chang et al.: "The Disease Progression of Mecp2 Mutant Mice Is Affected by the Level of BDNF Expression." Publishing in Neuron 49, 341-348, February 2, 2006. DOI 10.1016/j.neuron.2005.12.027

Cell Press

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