Fragile X protein acts as toggle switch in brain cells
New research shows how the protein missing in fragile X syndrome the most common inherited form of intellectual disability acts as a molecular toggle switch in brain cells.
The fragile X protein, called FMRP, hooks up with a group of molecules called microRNAs to switch the production of other proteins on and off in response to chemical signals, scientists at Emory University School of Medicine have discovered.
The results appear in the June 10 issue of Molecular Cell.
"For learning and memory to take place, neurons need to be able to make new proteins on demand, at particular synapses in a localized way," says senior author Gary Bassell PhD, professor of cell biology and neurology at Emory University School of Medicine. "It appears that FMRP has evolved to use microRNAs to control the synthesis of proteins at synapses."
The research team included the first author, Ravi Muddashetty PhD, and contributing co-authors, Vijayalaxmi Nalavadi PhD, Christina Gross PhD, Xiaodi Yao, Oscar Laur PhD and Lei Xing PhD. This research was done in collaboration with Stephen Warren PhD, professor and chair of the Department of Human Genetics.
In fragile X syndrome, FMRP's absence leads to overactive signaling and unregulated protein production at synapses, the junctions between brain cells where chemical communication occurs. This leads to structural changes at synapses and an impairment of cells' ability to respond to chemical signals, which in turn interferes with learning and memory.
Muddashetty and Bassell focused on a particular protein called PSD-95, whose production they had previously discovered was regulated by FMRP although they didn't know how FMRP exerted its control. PSD-95 appears to have an important role in anchoring together signaling molecules at synapses, the parts of neurons directly involved in learning and memory. Mice lacking the gene for PSD-95 develop normally but have more difficulty learning the location of a hidden platform in a water maze, compared with normal mice.
"The changes at synapses seen in fragile X syndrome are probably not caused by the overproduction of a single protein," Bassell says. "But we think that losing the ability to make PSD-95 on demand is an important component."
In cultured neurons, Muddashetty studied part of the RNA molecule encoding PSD-95, which responds to excitement by the neurotransmitter glutamate. This way he could dissect which proteins and RNA molecules were needed. Interfering with a particular microRNA, called miR-125, could stop the PSD-95 RNA from responding to glutamate signaling and could even drive neurons to produce more protrusions at their synapses.
MicroRNAs are involved in a process called RNA interference, whose discovery earned the 2006 Nobel Prize in Medicine. RNA interference is a way that short RNA molecules (microRNAs) can silence a stretch of genetic code.
These tiny RNA molecules have become a widely used laboratory tool for shutting off a specific gene. When the RNA molecules are introduced into the cell, they are actually hijacking a machine inside the cell called RISC (RNA-induced silencing complex). MicroRNAs normally govern the activity of RISC, which can prevent a given gene from being translated from RNA into protein.
In a sense, FMRP is acting as a "RISC manager." Together with microRNA, it clamps down on an RNA, preventing the synthesis of protein, until glutamate signals force them to loosen up. Thus, FMRP determines when the protein should be made at the synapses.
"Future work may uncover whether this is a general mechanism to guide specific miRNAs onto target mRNAs at synapses," the authors write.
The finding illustrates how microRNAs are emerging as key players in neurological development and disease, Bassell says. Since a given microRNA can regulate hundreds of targets, one potential drug strategy for fragile X syndrome would be to aim at restoring microRNA function.
More information: R.S. Muddashetty, V.C. Nalavadi, C. Gross, Xiaodi Yao, L. Xing, O. Laur, S.T. Warren; and G. Bassell. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation and mGluR signaling. Mol. Cell (2011).
Provided by Emory University
- New clue found for Fragile X syndrome-epilepsy link Apr 12, 2011 | not rated yet | 0
- Scientists identify new drug strategy against fragile X syndrome Aug 10, 2010 | not rated yet | 0
- Mechanism may explain aspects of brain impairment seen in Fragile X Syndrome Jun 09, 2008 | not rated yet | 0
- Fragile X protein loss alters brain pathways responsible for learning and memory Apr 08, 2010 | not rated yet | 0
- Newly identified mechanism for silencing genes points to possible anti-cancer strategies May 16, 2007 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
Nearly 20 percent of kidneys that are recovered from deceased donors in the U.S. are refused for transplant due to factors ranging from scarring in small blood vessels of the kidney's filtering units to the organ going too ...
Medical research 5 hours ago | 5 / 5 (1) | 0 |
Discovery of circadian clock in mice hair reveals period of time when damage from radiotherapy can be quickly repaired
Discovering that mouse hair has a circadian clock - a 24-hour cycle of growth followed by restorative repair - researchers suspect that hair loss in humans from toxic cancer radiotherapy and chemotherapy ...
Medical research 6 hours ago | 5 / 5 (2) | 1 |
Salamanders' immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts, scientists have ...
Medical research 7 hours ago | 5 / 5 (2) | 2 |
New research from the University of Southampton has shown that blind and visually impaired people have the potential to use echolocation, similar to that used by bats and dolphins, to determine the location of an object.
Medical research 9 hours ago | not rated yet | 1 |
A novel vaccine study from South Dakota State University (SDSU) will headline the groundbreaking research that will be unveiled at the American Association of Pharmaceutical Scientists' (AAPS) National Biotechnology Conference ...
Medical research 10 hours ago | not rated yet | 0
New research suggests that a compound abundant in the Mediterranean diet takes away cancer cells' "superpower" to escape death. By altering a very specific step in gene regulation, this compound essentially re-educates cancer ...
6 hours ago | 4.7 / 5 (7) | 1 |
Researchers have pinpointed a catalytic trigger for the onset of Alzheimer's disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons ...
7 hours ago | 5 / 5 (2) | 0 |
Turns out, that old "practice makes perfect" adage may be overblown. New research led by Michigan State University's Zach Hambrick finds that a copious amount of practice is not enough to explain why people ...
4 hours ago | 3.6 / 5 (5) | 0 |
Older prostate cancer patients with other underlying health conditions should think twice before committing to surgery or radiation therapy for their cancer, according to a multicenter study led by researchers in the UCLA ...
4 hours ago | not rated yet | 0 |
A new diagnostic test for a worm infection that can lead to severe enlargement and deformities of the legs and genitals is far more sensitive than the currently used test, according to results of a field ...
4 hours ago | not rated yet | 0 |