Navigation Links
Fail-safe system may lead to cures for inherited disorders
Date:9/15/2011

Scientists at the University of California, San Diego School of Medicine have uncovered a previously unknown fail-safe (compensatory) pathway that potentially protects the brain and other organs from genetic and environmental threats. The discovery could provide new ways to diminish the negative consequences of genetic mutations and environmental toxins that cause neurological diseases and other maladies.

The findings are published in the Sept. 16 issue of the journal Molecular Cell.

Messenger ribonucleic acid (mRNA) is an essential molecule that "reads" genetic information contained within the human genome, and based on this information, generates proteins essential for life. A key inherent feature of mRNA is its "stop signal," which tells cellular machinery to stop reading the mRNA because it has produced a full-length protein. Importantly, in some aberrant mRNAs, the stop signal is displayed too early, resulting in the production of a shorter-than-normal protein. Some of these short proteins can be highly toxic to cells. To avoid their production, cells use a quality control pathway called nonsense-mediated mRNA decay or NMD, which rapidly degrades "bad" mRNAs with early stop signals.

In research published earlier this year, Miles Wilkinson, PhD, professor of reproductive medicine and a member of the UCSD Institute for Genomic Medicine, and colleagues, revealed that NMD is important for the normal development of the brain and the nervous system. Jozef Gecz, PhD, professor of pediatrics at the University of Adelaide, showed that when NMD doesn't work correctly, neurological conditions arise, ranging from mental retardation and attention-deficit disorder to schizophrenia and autism. These conditions are likely due to the production and accumulation of short proteins in the brain.

Like all components of the body, the NMD pathway is vulnerable to insults, such as environmental toxins or gene mutations. "If such events prevent the NMD pathway from working, there will be an accumulation of short proteins, some of which are likely toxic, resulting in bad consequences to the individual," Wilkinson said.

In their present work, Wilkinson and colleagues report the discovery that human cells have evolved a way to overcome attacks on the NMD pathway. If any molecule of the pathway is injured, the cell sends reinforcement molecules to compensate for the loss.

"These reinforcements are not sent out from all cells of our body but only selectively in certain cells; in some cases they appear to be sent from cells that need reinforcements the most," Wilkinson said.

"This is an important feature of this compensatory ("buffering") response that could potentially be relevant for clinical application," Wilkinson said. "To appreciate this, one first needs to realize that a very large proportion of people with genetic diseasesone-third, in facthave a faulty gene with a mutation that leads to an early stop signal. As a consequence, most of these genes will give rise to an mRNA that is degraded by NMD and hence the encoded protein is never made. A key point is that a proportion of these mutant proteinsalthough shorter than normalis actually still functional. So, if clinicians could inhibit NMD, this would potentially ameliorate the symptoms of some of these diseases because this treatment would increase the production of these short, but still functional, proteins."

"Unfortunately, a global NMD blockade would also lead to the production of lots of other short proteins, some of which would be toxic," Wilkinson noted. As a result, "in the past, there has been little interest in 'NMD-inhibition therapy.'" The new discovery makes NMD-inhibition therapy much more attractive because the tissue-specific compensatory response has the potential to greatly dampen the side effects. "By choosing a branch of the NMD pathway that is subject to compensation only in the appropriate tissues, a highly selective effect can potentially be achieved" said Wilkinson.

"For example, there is a need to come up with better treatments for cystic fibrosisa heritable chronic lung diseasethat is currently being treated in some patients with drugs that act by blocking recognition of the premature stop signal in the mutant CFTR gene," he said. "There has been some success with this approach, but there are concerns with side effects." The finding that NMD is buffered by a tissue-specific regulatory system means that one could design a different type of druga tissue-specific NMD-inhibition drugthat increases the level of the CFTR protein primarily in its main cellular site of action: the lung. "This could potentially increase the efficacy and drastically reduce the side effects of NMD-inhibition drugs" says Wilkinson.


'/>"/>

Contact: Scott LaFee
slafee@ucsd.edu
619-543-6163
University of California - San Diego
Source:Eurekalert

Related biology news :

1. The battle of the morphogens: How to get ahead in the nervous system
2. Database of water, wastewater pipeline infrastructure systems to be launched Sept. 1
3. Researchers on the trail of a treatment for cancer of the immune system
4. A mold on which to create new parts of the puzzle that is the nervous system
5. National Center for Systems Biology to be established at Medical College
6. Scientists explore the role of aeroecology in bat conservation and ecosystem health
7. Most plant species important in various and varying ecosystems: ISU research
8. Trauma drama: K-State professor researches drama queen of immune system
9. Guam researcher studies Mount Pinatubo ecosystem recovery
10. GTSI Wins Department of Defense Contract to Provide Biometric Automated Toolset Systems for U.S. Army
11. IOF urges systematic osteoporosis management after vertebral fracture augmentation
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/25/2016)... , Jan. 25, 2016  Glencoe Software, the ... pharma and publication industries, will provide the data management ... Centre (NPSC). ... Phenotypic analysis measures ... whole organisms, allowing comparisons between states such as health ...
(Date:1/21/2016)... January 21, 2016 ... new market research report "Emotion Detection and Recognition Market by ... Tools (Facial Expression, Voice Recognition and Others), Services, ... forecast to 2020", published by MarketsandMarkets, the global ... reach USD 22.65 Billion by 2020, at a ...
(Date:1/20/2016)... 20, 2016  Synaptics Incorporated (NASDAQ: SYNA ... today announced sampling of S1423, its newest ClearPad ... small screen applications including smartwatches, fitness trackers, and ... and rectangular shapes, as well as thick and ... moisture on screen, while wearing gloves, and supports ...
Breaking Biology News(10 mins):
(Date:2/12/2016)... MedGenome,s Commitment Will Help ... of Complex Diseases Such as Cancer, Metabolic Disorders, ... --> --> MedGenome, the market ... leading provider of genomics research services globally, today ... GenomeAsia 100K consortium as a founding member. ...
(Date:2/11/2016)... -- Vermillion, Inc. (NASDAQ: VRML ), a bio-analytical solutions ... of the Steering Committee for its Pelvic Mass Registry. ... Pelvic masses can present physicians and healthcare professionals with ... ruled out, pelvic masses may include cancers of the ... tumors and gastrointestinal and urinary tract masses. ...
(Date:2/11/2016)...  Spectra BioPharma Selling Solutions (Spectra) is a ... companies the experience, expertise, operational delivery and customer ... teams. Created in concert with industry leading commercial ... and tactical needs of its clients by providing ... personal and non-personal promotion. --> ...
(Date:2/11/2016)... 2016  Dovetail Genomics™ LLC today announced that it ... a planned metagenomic genome assembly service. Richard Green ... assembly method in a talk on Friday, February 12 ... conference in Orlando, Fla. ... is difficult. Using its proprietary Chicago ...
Breaking Biology Technology: