New drug target for Rett syndrome

Researchers have identified a faulty neural pathway that can be corrected in mice to releave symptoms of Rett syndrome.

Rett syndrome is a relatively common neurological disorder. It is the second most common cause of intellectual disability in girls after Down's syndrome and is associated with a dysfunctional gene on the X chromosome. Austrian physician Andreas Rett first described the disorder in 1966, but it wasn't until 1999 that Huda Zoghbi and her lab at Baylor College of Medicine, identified mutations in the gene MECP2 as the root cause of Rett syndrome.

Unlike females, who have two X chromosomes, males have an X and a Y chromosome. Because males lack a "backup" copy of the X chromosome that can compensate for their defective one, flaws in MECP2 are often lethal to them. RTT occurs in a variety of racial and ethnic groups worldwide and is now known to occur in 1:10,000 to 1:23,000 female births, but its incidence may be far greater as new genetic evidence is discovered.

Development appears normal until 6-18 months of age, followed by loss of acquired speech and hand skills, slowing of head growth and stereotyped repetitive hand movements such as hand washing, hand wringing, hand tapping, hand clapping and hand mouthing. Stereotyped hand movements may change over time and additional problems may include seizures, breathing irregularities (hyperventilation and apnea), teeth grinding and curvature of the spine (scoliosis). Usually this is prenatally lethal to the fetus.

MECP2 turns a very large number of genes on and off throughout the entire body, so it has been a longstanding puzzle why girls, and on occassion a rare boy, with Rett syndrome have this very specific, developmental brain disorder.

The new findings from Harvard Stem Cell Institute (HSCI) could lead to the discovery of compounds or drugs to radically benefit children affected by the disease, according to neurobiologist Jeffrey Macklis PhD, who directed the work. Dr. Macklis is the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology, Center for Brain Science, at Harvard University.

The research is published online in Nature Communications Nature Communications. Noriyuki Kishi and Jessica MacDonald, both recent postdoctoral fellows in the Macklis laboratory, are co-first authors.

"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 we could fix. But, if we found a disrupted, improperly regulated signaling pathway that was 'drug-able,' we might be able to make them functionally better with already available therapeutics - which might make a difference in their and their families' lives."

Jeffrey Macklis PhD, member of HSCI's Executive Committee, former Program Head of HSCI's Nervous System Diseases Program, and an Allen Distinguished Investigator of the Paul G. Allen Family Foundation.

Instead of concentrating on the MECP2 gene, Macklis' group focused on neurons Macklis knew were "abnormal and implicated in Rett syndrome and autism spectrum disorders."  In 2004, his lab was the first to describe abnormal development in a type of neuron responsible for communicating signals between the two hemispheres of the brain. These neurons, called inter-hemispheric callosal projection neurons (CPN), have shorter, less developed dendrites or "receiving antennas" in mice with the Rett gene mutations, as do individuals with Rett syndrome.

Building on their 2004 findings, the team was able to fluorescently label CPN in mice with or without the Rett mutation, purifying the CPN neurons from other types of neurons. This allowed them to see the level at which genes were made active, and therefore how much of the proteins coded for by those those genes was also being made.

They found the gene for IRAK1, and identified it to be regulated by MECP2 a well-known part of the NF-kB signaling pathway. The IRAK1 gene was making about three times more protein than normal.

Modifying IRAK1 levels in mice with Rett mutations and in mouse neurons in culture dishes, reduced the Irak1 gene activity by roughly half. Consequently, IRAK1 protein also made neurons and their dendrites develop substantially better. They were almost indistinguishable from normal when measured by several assays. The mice also had significantly fewer symptoms, better function, and a much longer lifespan.

Macklis adds that researchers have started looking into potential compounds and drugs which may already be available. Such compounds might partially correct the IRAK1 neural pathway, and might ultimately ameliorate the affects of Rett syndrome.

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

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Toddler with Rett syndrome.
Image Credit: Rett Syndrome.org