NFXF Scientific & Clinical Advisory Committee member Dr. Elizabeth Berry-Kravis had the following to share about the ScienceDaily report recently published.

This news article is a little confusing when it implies that treatments for Fragile X syndrome (FXS) would also help patients with Down Syndrome (DS). The pathway in the system studied in the EMBO Journal article actually goes in the opposite direction in DS and FXS. This would suggest that reduction of FMRP (like in FXS) would actually treat aspects of DS. Indeed they show that DSCR1, a protein made to excess in DS due to the extra chromosome 21, is bound and regulated by FMRP and particularly interacts with a specific form of FMRP. An excess of DSCR1 causes dendritic spines to be enlarged (more mushroom shaped than they should be), while loss of FMRP causes the spines to become long and thin (immature). So in theory something that treats FXS and normalizes spines in FXS should actually make the problem in DS worse, and something that treats DS should make FXS worse – it’s all about the balance in the pathway and getting that just right. (Not just whether things act in the same pathway.)

This makes sense as the new GABA drugs in clinical trials for FXS and DS actually manipulate the signaling in opposite direction – the DS drugs are GABA blockers and the FXS drugs are activators of very specific kinds of GABA receptors. So the DS drug decreases the brain inhibitory activity of GABA while the FXS drugs (specifically arbaclofen, acamprosate and ganaxolone) increase the brain inhibitory activity of GABA.

So we have to be careful not to imply that the treatments will always be the same because there are pathway overlaps, rather the pathway overlaps that we identify through neuroscience progress, in articles like this one, will teach us which direction to modulate a given pathway pharmacologically, to develop disease-specific treatments. Also, of course, with a whole chromosome duplicated in DS, DSCR1 will not be the only mechanism active in DS.

Here is the original article as it appeared in ScienceDaily on (Aug. 3, 2012).

Fragile X and Down Syndromes Share Signalling Pathway for Intellectual Disability

Dendritic spines

Dendritic spines are essential for intellectual ability. (Credit: Image courtesy of EMBO - excellence in life sciences)

ScienceDaily (Aug. 3, 2012) – Intellectual disability due to Fragile X and Down syndromes involves similar molecular pathways report researchers in The EMBO Journal. The two disorders share disturbances in the molecular events that regulate the way nerve cells develop dendritic spines, the small extensions found on the surface of nerve cells that are crucial for communication in the brain.

“We have shown for the first time that some of the proteins altered in Fragile X and Down syndromes are common molecular triggers of intellectual disability in both disorders,” said Kyung-Tai Min, one of the lead authors of the study and a professor at Indiana University and the Ulsan National Institute of Science and Technology in Korea. “Specifically, two proteins interact with each other in a way that limits the formation of spines or protrusions on the surface of dendrites.” He added: “These outgrowths of the cell are essential for the formation of new contacts with other nerve cells and for the successful transmission of nerve signals. When the spines are impaired, information transfer is impeded and mental retardation takes hold.”

Intellectual disability is a developmental brain disorder that leads to impaired cognitive performance and mental retardation. Two of the most prevalent genetic causes of intellectual disability in humans are Fragile X and Down syndromes. Fragile X syndrome arises from a single gene mutation that prevents the synthesis of a protein required for neural development (Fragile X mental retardation protein). The presence of all or a part of a third copy of chromosome 21 in cells causes Down syndrome. Although both syndromes arise due to these fundamental genetic differences, the researchers identified a shared molecular pathway in mice that leads to intellectual disability for both disorders.

The mice that were used in the experiments are model systems for the study of Fragile X syndrome and Down syndrome. Down syndrome mice have difficulties with memory and brain function, and the formation of the heart is often compromised, symptoms that are also observed in humans with Down syndrome. Both model systems are very useful to scientists looking to dissect the molecular events that occur as the disorders take hold.

The scientists revealed that the Down syndrome critical region 1 protein (DSCR1) interacts with Fragile X mental retardation protein (FMRP) to regulate dendritic spine formation and local protein synthesis. By using specific antibodies that bind to the proteins as well as fluorescent labeling techniques they showed that DSCR1 specifically interacts with the phosphorylated form of FMRP. The overlapping molecular pathways of intellectual disability in both genetic disorders suggest that a common therapeutic approach might be feasible for both syndromes.

Min remarked: “We believe these experiments provide an important step forward in understanding the multiple roles of DSCR1 in neurons and in identifying a molecular interaction that is closely linked to intellectual disability for both syndromes.”