080210xf's Blog

L'X fragile sera vaincu | Fragile X will be conquered

Archive for July, 2011

Fragile X protein found to regulate key autism candidates

Deborah Rudacille, Sfari.org |

FMRP, the protein missing in fragile X syndrome, regulates the activity of more than 800 other proteins, including some key players in autism, according to a study published last week inCell1. Many of these autism-associated proteins cluster on either side of the synapse, the junction between neurons.

Fragile X syndrome is an inherited form of mental retardation caused by a full or partial loss of function of the FMR1 gene on the X chromosome. It is twice as prevalent in males as in females. About one-third of individuals with the syndrome show features of autism, including trouble interacting with others, maintaining eye contact and learning to speak.

Studies have shown that mice lacking FMRP, or fragile X mental retardation protein, have immature dendritic spines, the neuronal branches that receive signals from other cells2,3, and too little of some synaptic proteins4.

The new study shows that FMRP regulates these synaptic proteins by blocking the action of ribosomes. Ribosomes are cellular structures that translate messenger RNA (mRNA), the transcript of genetic information, into protein. FMRP acts like a brake on this process, limiting the amount of protein produced by its targets.



Workings of brain protein suggest therapies for inherited intellectual disability, autism

Cell Press via Eureka Alert |

Researchers now have a much clearer understanding of how mutations in a single gene can produce the complex cognitive deficits characteristic of Fragile X Syndrome, the most common inherited form of intellectual disability. As the majority of patients with Fragile X Syndrome also display autism-like symptoms, the findings offer hope for treating both conditions.

A report in the July 22nd issue of the journal Cell, published by Cell Press, defines a set of messenger RNA (mRNA) molecules that the Fragile-X mental retardation protein (FMRP) binds in the brains of mice. Many of these mRNAs encode proteins that function at neurons’ connection points. When properly bound, FMRP prevents the translation of these mRNAs into proteins until the time is right.

“By understanding for the first time the direct targets of FMRP and its actions, we open up a whole world of potential avenues for therapies designed to make kids with Fragile X or autism better,” said Robert Darnell, a Howard Hughes Medical Institute investigator at The Rockefeller University.

“The power comes from taking two diseases with similar symptoms and looking at what is in common,” added Jennifer Darnell, also at The Rockefeller University. Of the almost 850 identified targets of FMRP, she explained, it is likely only a much smaller subset has a real impact on health or disease.

The Darnell team’s breakthrough uses a technique they developed a few years ago based on a “biochemical trick”. They use ultraviolet light to solidify the bonds between a protein, in this case FMRP, and the mRNAs it binds. Those protein-mRNA complexes could then be isolated and sequenced to reveal a “beautiful map” of the mRNA transcripts and precisely where they are bound to FMRP.

The experiments reveal that FMRP specifically binds to the protein-coding portions of those brain mRNAs. Jennifer Darnell said that distribution is unlike what they’ve seen before and looked much like the distribution of ribosomes, the cellular components that assemble proteins.

Further experiments suggest that FMRP acts as a “brake,” reversibly stalling ribosomes after they bind mRNA. Robert Darnell likened FMRP to the nozzle at the end of a hose. It allows the mRNA transcripts to be loaded with ribosomes in the locations where they will be needed, and when the time is right, bursts of translation (protein synthesis) can occur. That sort of tight control is likely to be critical for the formation and plasticity of neural connections, the cellular foundation for learning and memory.

Their basic scientific discoveries suggest two different overall strategies for treating Fragile X Syndrome: by lowering the activity of particular proteins normally kept under wraps by FMRP or by replacing FMRP’s ability to stall ribosomes. Notably, the Darnells say the latter is exactly what antibiotics do to slow the growth of bacteria.

“We may be able to take the edge off of the extra protein synthesis,” Jennifer Darnell said.

Ultimately, there will be more to the story, Robert Darnell added. “FMRP is one of many regulatory proteins in the neuron. It doesn’t work all by itself.”


Mouse study raises questions about fragile X treatment

Deborah Rudacille, Sfari.org |

Blocking a chemical messenger — a much-touted approach to treating fragile X syndrome — is unlikely to completely reverse symptoms of the disorder, according to a provocative new study1.

Multiple drug candidates in clinical trials to treat fragile X syndrome are based on blocking group 1 metabotropic glutamate receptors (mGluR), a set of chemical messenger receptors involved in cell signaling. Animal studies, including an influential 2007 report2, have shown that reining in the runaway signaling by these receptors decreases seizures and other manifestations of over-excitation of the brain.

In the new study, published online in May in Behavioural Brain Research, researchers cut expression of mGluR1 and mGluR5 by half using a genetic approach rather than chemical inhibitors. The 2007 study used the same approach, but this time, the researchers saw an increase in seizures and only modest behavioral improvements.


UIC to Study Medication for Autism Spectrum Disorders

An experimental drug to treat social withdrawal in children and young adults with autism is being studied in a clinical trial at the University of Illinois at Chicago’s Institute for Juvenile Research.

Children with autism — or autism spectrum disorders — often have difficulty communicating and interacting with others. Although behavioral and psychological interventions are often beneficial, currently there is no medication to address social communication difficulties, a core symptom of ASD.

A drug treatment is needed that would address symptoms that are “often disabling for patients and families,” says Dr. Edwin Cook, professor of psychiatry and director of autism and genetics at UIC.

UIC is the only study site in Illinois and one of 25 sites nationwide. The study is sponsored by Seaside Therapeutics, Inc.

The clinical trial will enroll approximately 150 patients diagnosed with autism spectrum disordersbetween ages 5 and 21 to evaluate the efficacy, safety, and tolerability of STX209 (arbaclofen).

Participants in the 22-week study will be randomized to receive either the study drug, STX209, or a placebo. The clinical trial will include screening, treatment, withdrawal of medication, and a follow-up period. Subjects who complete the study may be eligible to enroll in a subsequent open-label study in which all subjects are treated with STX209.


Fragile X Culprit Fails to Keep Protein Production Under Control

New laboratory studies indicate that the neurological problems caused by Fragile X syndrome, the most common form of inherited intellectual disability, may be due to excess synthesis of certain neuronal proteins that must be present at exactly the right time and place for an individual to learn.

In patients with Fragile X syndrome, which affects approximately one in 5,000 males and half that number of females worldwide, mutations in the gene encoding the Fragile X mental retardation protein (FMRP) can cause cognitive dysfunction and facial abnormalities, among other symptoms. The majority of children with Fragile X syndrome also exhibit behaviors typically associated with autism.

“This work closes a loop between molecular biology and human cognition.”

Robert B. Darnell


Clinical trial for fragile X syndrome treatment

health.universityofcalifornia.edu |

UC Davis will participate in a nationwide trial targeting adolescents and young adults with fragile X syndrome.

The UC Davis MIND Institute is participating in a nationwide, multicenter clinical trial of an investigational medication that has shown clinically meaningful improvements in social functioning in adolescents and young adults with fragile X syndrome.

“This investigational drug has the potential to play a much-needed role in improving the core symptoms of fragile X syndrome and helping patients and families achieve an improved quality of life,” said Randi Hagerman, medical director of the UC Davis MIND Institute and the clinical trial lead investigator.

The medication is known as STX209, or Arbaclofen. It is an oral selective gamma-amino butyric acid type B (GABA-B) receptor agonist being developed by Seaside Therapeutics Inc. of Cambridge, Mass., which is sponsoring the trial.

The study will measure the efficacy, safety and tolerability of Arbaclofen for patients between 12 and 25 years of age with fragile X syndrome, who will receive the medication or a placebo followed by a withdrawal period. The UC Davis MIND Institute will enroll 12 participants.

Fragile X syndrome is the leading genetic cause of intellectual disability and the leading single-gene cause of autism. It is the result of the mutation of a single gene, the fragile X mental retardation 1 (FMR1) gene on the X chromosome.

The FMR1 gene produces a protein needed for normal brain development. Individuals with fragile X syndrome lack this protein and, as a result, the majority of affected individuals have significant intellectual disabilities and require lifetime care.

There currently are no Food and Drug Administration (FDA)-approved treatments for patients with fragile X syndrome.

For further information concerning the clinical trial, please contact Lindsey Partington at (916) 703-0471 or lindsey.partington@ucdmc.ucdavis.edu.

At the UC Davis MIND Institute, world-renowned scientists engage in research to find improved treatments as well as the causes and cures for autism, attention-deficit/hyperactivity disorder, fragile X syndrome, Tourette syndrome and other neurodevelopmental disorders. Advances in neuroscience, molecular biology, genetics, pharmacology and behavioral sciences are making inroads into a better understanding of brain function. The UC Davis MIND Institute draws from these and other disciplines to conduct collaborative, multidisciplinary research. For more information, visit mindinstitute.ucdavis.edu.