Reducing NF-KappaB Signaling Ameliorates Neurological Symptoms in Rett Syndrome Mouse Model

By tracing the molecular pathway linked to the neurological disorder Rett syndrome, researchers have identified molecular pathway that seems to be a potential drug target for alleviating symptoms of the condition.

Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene, methyl CpG binding protein 2 (MECP2) on the X chromosome. Boys with Rett syndrome are rare, because male fetuses carrying the mutations on their one X chromosome usually die before birth. Patients (mostly girls) with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors.


Since MECP2, which is mutated in Rett syndrome, regulates a very large number of genes, investigators at Harvard University (Cambridge, MA, USA) looked at genes that functioned downstream of the Mecp2 protein in the molecular circuitry of the cerebral cortex and identified upregulation of Irak1, a central component of the NF-kappaB pathway. Irak1 is one of two putative serine/threonine kinase enzymes that become associated with the interleukin-1 receptor (IL1R) upon stimulation. This gene is partially responsible for IL1-induced upregulation of the transcription factor NF-kappaB.

The investigators reported in the January 29, 2016, online edition of the journal Nature Communications that abnormal Mecp2-null cortical callosal projection neurons in a Rett syndrome mouse model produced about three times more Irak1 protein than was produced by normal neurons, and that NF-kappaB signaling was upregulated in the cortex of mice with Mecp2 loss-of-function. Genetically reducing NF-kappaB signaling in Mecp2-null mice ameliorated CPN dendritic complexity and substantially extended the abnormally shortened lifespan of these neurons.

These results provided new insight into the fundamental neurobiology of Rett syndrome and suggested potential therapeutic strategies via modulation of the NF-kappaB pathway.

"My view was that MECP2 mutation in Rett syndrome disrupts so many genes and their protein products that we were not going to find a single gene that we could fix to help girls with Rett," said senior author Dr. Jeffrey Macklis, professor of life sciences at Harvard University. "But if we found a disrupted, improperly regulated signaling pathway that was "drug-able," that affected enough of the girls' pathology, we might be able to make them dramatically functionally better with already available therapeutics, and that might make a real difference in their lives and their families' lives."

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