Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Double effort against Rett's syndrome

20.12.2016

The trick against haploinsufficiencies: Getting the 'single' gene to work for 2

Imagine that a colleague of yours has fallen ill and will be absent for a while from the office. What do you do? Do you go on working at your usual pace and by doing so risk a huge backlog of work that will affect the performance of the whole office, or do you roll up your sleeves and get down to it (perhaps also after your boss has motivated you by promising some benefit) by doubling your efforts and doing your absent colleague's work as well as your own?


The rat's brain areas stimulated in the study.

Credit: SISSA

Something similar occurs with genes when their homologues are missing, a condition doctors call haploinsufficiency. When this abnormality manifests, especially when it concerns genes that have an important function in the central nervous system, it may lead to very serious diseases, such as Rett's syndrome that causes severe progressive mental retardation related to the FOXG1 gene.

A group of researchers at the International School for Advanced Studies (SISSA) in Trieste, led by Antonello Mallamaci, has decided to adopt the "motivational" boss strategy by stimulating the surviving FOXG1 gene to work more to compensate for the absence of the missing gene.

... more about:
»RNA »SISSA »nervous »nervous system »neurons

"By using viral vectors to insert into neurons RNA fragments targeting the gene's regulatory sequences, we "gently" stimulated the gene to do more work, in particular nearly double", explains Mallamaci. "Note that we don't want the gene to do more than that. If it worked, say, three times as much, it could cause even worse damage". In fact, it is known that when three copies of the FOXG1 exist (one more than normal), we have West's syndrome, which is perhaps even worse as it causes a severe form of epilepsy. "It's therefore vital that the gene we stimulate does no more than about double the normal amount of work".

The method adopted by the Trieste group is a "cunning" solution to the treatment problems posed by these diseases. "Stimulating the normal gene allows us to preserve its natural endogenous regulation", explains Mallamaci. Genes in fact are not expressed everywhere and at the same intensity: to the contrary, in many body tissues they are silenced, in others their activity is time-modulated with great precision. If their regulation were to be disrupted, it is easy to imagine the chaos that this would generate. "Going back to the office worker's metaphor, it's like having an inexperienced intern do the absent worker's job: at best he won't do anything, at worst he'll mess things up. Instead, asking an experienced colleague, who's familiar with the office's processes and rhythms, to work harder, offers greater guarantees".

Multiple tests

The team ran several tests. First, in vitro, the scientists checked whether stimulation through promoter RNA was able to amplify gene activity only where it was needed. "FOXG1 is only active in the anterior brain and we absolutely don't want it to act elsewhere in the nervous system or the body", explains Mallamaci. "The tests gave positive results: after stimulation, the gene continued to be expressed only in cells where it had previously been active and remained silent in tissues where it normally doesn't work. Very importantly, the activity observed increased by a factor not far from 2, i.e. that "double" expression that we were trying to achieve".

The second test, also in vitro, demonstrated that the gene's endogenous regulatory mechanisms related to the electrical activity of the neurons expressing it are not altered by stimulation with RNA: "we saw a rise in the gene's activity, but the shape of the time-activity curve was basically unchanged, a clear indication that regulation remains the same", explains Cristina Fimiani, PhD student in Functional and Structural Genomics at SISSA and co-first author of the study.

The third step was to see whether the stimulation also worked in vivo. "The test was done on healthy mice and we found that the stimulation was even more effective in vivo than in vitro," Mallamaci concludes.

"We're still at the beginning of a very long clinical process that might one day lead to treatment", he adds. "The results, though, are very clear and definitely encourage us to continue this line of research. The next steps will be in vivo tests on animal models affected by the disease".

What makes these therapies so interesting for the future? "Rett's disease is rare and affects only a small number of patients, so it doesn't attract the attention and investments of major pharmaceutical companies", concludes the scientist. "But, taken together, haploinsufficiencies affect very many people. The methodology we present in this study is therefore a test for a general method capable of fighting the large number of haploinsufficencies affecting the nervous system, and once developed it could be easily adapted to different genes".

Media Contact

Federica Sgorbissa
pressoffice@sissa.it
39-040-374-7644

 @sissaschool

http://www.sissa.it 

Federica Sgorbissa | EurekAlert!

Further reports about: RNA SISSA nervous nervous system neurons

More articles from Health and Medicine:

nachricht Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania

nachricht The strange double life of Dab2
10.01.2017 | University of Miami Miller School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

17.01.2017 | Materials Sciences

Smart homes will “LISTEN” to your voice

17.01.2017 | Architecture and Construction

VideoLinks
B2B-VideoLinks
More VideoLinks >>>