Signaling pathway and Rett syndrome

Harvard Stem Cell Institute (HSCI) researchers have identified a faulty signaling pathway that, when corrected in mice, ameliorates the symptoms of Rett syndrome, a devastating neurological condition. The findings could lead to the discovery of compounds or drugs that may benefit children affected by the disease, says neurobiologist Jeffrey Macklis, a member of the HSCI Executive Committee.
The research was published recently in Nature Communications. Noriyuki Kishi and Jessica MacDonald, both recent postdoctoral fellows in the Macklis laboratory, are co-first authors. Macklis, who directed the work, is the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science at Harvard University...

“My view was that MECP2 mutation in Rett syndrome disrupts so many genes and their protein products that we weren’t going to find a single gene that we could fix to help girls with Rett,” said Macklis, former program head of HSCI’s Nervous System Diseases Program, and an Allen Distinguished Investigator of the Paul G. Allen Family Foundation. “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.”

Instead of concentrating on the MECP2 gene, Macklis’ group focused on neurons he knew were “abnormal and implicated in Rett syndrome and autism spectrum disorders,” and in 2004, his lab was the first to describe abnormal development in this type of neuron. These neurons, called inter-hemispheric callosal projection neurons (CPNs), have shorter, less-developed dendrites, or “receiving antennas,” in mice with the Rett gene mutations and in individuals with Rett syndrome.

Building on their 2004 findings, the researchers were able to fluorescently label CPNs in mice with or without the Rett mutation, purify them from other types of neurons, and look at the levels at which many thousands of genes were active, and thus how much of the proteins coded for by those those genes was made.

They found that one gene for IRAK1, which Macklis’ group identified as regulated by MECP2 and which is a well-known part of the NF-kB signaling pathway, was making about three times more protein than normal. They modified IRAK1 levels both in mice with Rett mutations and in mouse neurons in culture dishes. When they reduced the activity of its gene Irak1 by roughly half, and consequently the amount of IRAK1 protein made, the neurons and their dendrites developed substantially better, indistinguishable from normal by several assays. Further, mice with reduced levels of IRAK1 had significantly fewer symptoms, better function, and much longer lifespan. They had much-improved health, well beyond only these neurons.

Now, Macklis said, the researchers have started looking into potential compounds and drugs that are already available and that might partially correct this pathway, and what dosages and timing might ultimately ameliorate the effects of Rett syndrome.

http://news.harvard.edu/gazette/story/2016/02/new-drug-target-for-rett-syndrome/
Courtesy of Neurologist Connect

Kishi N, MacDonald JL, Ye J, Molyneaux BJ, Azim E, Macklis JD. Reduction of
aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null
mice. Nat Commun. 2016 Jan 29;7:10520.

Abstract

Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation.