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Potential new target for treatment of Rett syndrome

October 10, 2015

The finding is published in the latest edition of the international journal Neurology.

Dr Helen Leonard, who heads the Australian Rett Syndrome Study at the Telethon Institute for Child Health Research, said the finding was exciting in that it identifies a potential new target for treatment of the debilitating neurological disorder.

"We know that there is a wide range in the onset and severity of symptoms in patients with Rett syndrome but it has been difficult to give families a firm idea of how the disorder would progress," Dr Leonard said.

"This information is potentially helpful in predicting the clinical progression, but importantly, gives us another area to explore for potential therapies."

In the study, clinical information and DNA samples were gathered from 125 patients from the Australian Rett Syndrome Database and an Israeli cohort coordinated by Dr Bruria Ben Zeev at the Safra Pediatric Hospital, Sheba Medical Centre, Sackler School of Medicine, Tel Aviv. The genetic testing was undertaken by Professor John Christodoulou, from the NSW Centre for Rett Syndrome Research at the Children's Hospital at Westmead in Sydney and Dr Eva Gak from the Sagol Neuroscience Center at the Sheba Medical Centre.

Professor Christodoulou said while it has been established that Rett syndrome is caused by mutations in the MECP2 gene, these new findings have established a correlation between the severity of clinical symptoms and a common brain-derived neurotrophic factor (BDNF) polymorphism.

"Those patients with the normal BDNF genetic variant had less severe symptoms, with later onset and frequency of seizures," Dr Christodoulou said.

"We know that BDNF plays a major role in the development, survival and function of brain cells. What we now have to establish is the nature of the interaction between MECP2 and BDNF."

"It may be that if we can stimulate BDNF within patients with Rett syndrome, there is a chance that we can delay the onset of seizures and reduce some of the more debilitating aspects of the disorder."

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"The role of p75 had been controversial for some time, but based on the evidence at the time, we expected to see indications that it mediates beta amyloid neurotoxicity," says co-first author Tasha Bengoechea, Ph.D., a former graduate student in Lee's lab. "We thought removing p75 while overexpressing amyloid would have a positive effect on neuron viability. The opposite was true."

Along with profound motor problems, the p75-deficient mice exhibited severe defects in the wiring of nerves to multiple organs, and the majority died within just three weeks. (Mice normally live up to two years.) When the researchers scaled down the production of toxic beta amyloid by deleting one copy of BACE1, which encodes the molecular shears that make the first cut in the production of beta amyloid fragments, the nerves in the sympathetic nervous system of p75-deficient mice were substantially restored.

"This is the first time the interplay between p75 and beta amyloid in the peripheral sympathetic system, a system that has not been paid much attention before, has been demonstrated," adds postdoctoral researcher and co-first author Zhijiang Chen, Ph.D. "Our findings will ultimately help to design novel strategies to treat the symptoms of the Alzheimer's disease and improve the quality of life for Alzheimer's disease patients."

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