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Trembling hands and molecular handshakes
October 26, 2009A novel protein structure involved in hereditary neurodegeneration
Fragile X tremor/ataxia syndrome (FXTAS) is a recently recognized condition, which is actually one of the most prevalent heritable neurodegenerative diseases. It is assumed that the condition is caused by deficiency for the protein Pur-alpha, which is essential for normal neural function. Structural studies undertaken by a team under the leadership of Dr. Dierk Niessing of the Helmholtz Zentrum München and the Gene Center at Ludwigs-Maximilians-University (LMU) have now determined the three-dimensional structure of Pur-alpha, and gained insights into the molecular function of the protein. The findings provide a possible basis for the development of an effective therapy for the disease.(PNAS Early Edition, 21. Oktober 2009)
Most FXTAS patients are males, and symptoms of the condition become manifest around the age of 55. As the disease progresses, patients develop tremor in their hands and also show ataxia, i.e. they have difficulty maintaining their balance when they move, and therefore have a tendency to fall. Quite often these deficits are accompanied by cognitive defects and dementia.
The underlying cause of FXTAS is a mutation in the gene for FMRP (Fragile X Mental Retardation Protein). This mutation is found on the X chromosome in one out of 800 men, and involves abnormal expansions of a DNA sequence composed of repeats of the base triplet CGG. Healthy people have between 5 and 54 copies of this sequence, while those who will develop FXTAS are born with between 55 and 200 repeats. Expansion of the triplet sequence beyond 200 copies leads to Fragile X Syndrome (FXS), which is the second most common cause of hereditary mental retardation after Down's syndrome. FXTAS itself is apparently triggered by a lack of the protein Pur-alpha. This protein binds to the CGG sequences in FMR messenger RNAs (mRNA). The excessive numbers of CGG triplets found in the mutant FMRP mRNA essentially bind so much Pur-alpha that insufficient amounts are available for its normal cellular function.
Dr. Niessing's team reports in the online Early Edition of the journal Proceedings of the National Academy of Sciences USA (PNAS) that the Pur-alpha protein itself consists of three copies of a structural unit called the PUR repeat. "The crystal structure of Pur-alpha will make it possible to understand the protein's function in detail, and this could contribute to the development of a therapy for FXTAS", says Dierk Niessing, who leads a junior research group that is jointly funded by the Helmholtz Zentrum München, the Helmholtz Association and LMU's Gene Center. "With the treatment options we have at the moment, we can only alleviate the symptoms but cannot attack the real cause of the disease."
"A PUR repeat looks like a hand: four so-called beta-strands, corresponding to four fingers, form a beta-sheet, and an adjacent alpha-helix resembles a thumb", explains Almut Graebsch, the first author from Niessing's group. Pairs of PUR repeats bind to each other in a particular configuration that is reminiscent of a handshake, forming a functional unit. In addition to X-ray diffraction, the researchers have used a technique called small angle X-ray scattering, which revealed that the Pur-alpha protein forms dimers - two molecules of the protein bind stably to one another. This probably occurs when PUR repeats in separate molecules interact, in a similar way to the repeats within a molecule, to form the handshake structure.
Experiments in animals have shown that the symptoms of FXTAS disappear if extra Pur-alpha is supplied. "Perhaps the condition can be cured if one can find a way of stopping Pur-alpha from binding to long stretches of CGG in mRNA", says Niessing. By mutating the protein, his group has already obtained clues to how Pur-alpha binds to the CGG repeats. The next step is to find out precisely how Pur-alpha binds to RNA. This in turn could suggest ways of preventing the interactions that cause the disease. (HHZM)
Ludwig-Maximilians-Universität München
The underlying cause of FXTAS is a mutation in the gene for FMRP (Fragile X Mental Retardation Protein). This mutation is found on the X chromosome in one out of 800 men, and involves abnormal expansions of a DNA sequence composed of repeats of the base triplet CGG. Healthy people have between 5 and 54 copies of this sequence, while those who will develop FXTAS are born with between 55 and 200 repeats. Expansion of the triplet sequence beyond 200 copies leads to Fragile X Syndrome (FXS), which is the second most common cause of hereditary mental retardation after Down's syndrome. FXTAS itself is apparently triggered by a lack of the protein Pur-alpha. This protein binds to the CGG sequences in FMR messenger RNAs (mRNA). The excessive numbers of CGG triplets found in the mutant FMRP mRNA essentially bind so much Pur-alpha that insufficient amounts are available for its normal cellular function.
Dr. Niessing's team reports in the online Early Edition of the journal Proceedings of the National Academy of Sciences USA (PNAS) that the Pur-alpha protein itself consists of three copies of a structural unit called the PUR repeat. "The crystal structure of Pur-alpha will make it possible to understand the protein's function in detail, and this could contribute to the development of a therapy for FXTAS", says Dierk Niessing, who leads a junior research group that is jointly funded by the Helmholtz Zentrum München, the Helmholtz Association and LMU's Gene Center. "With the treatment options we have at the moment, we can only alleviate the symptoms but cannot attack the real cause of the disease."
"A PUR repeat looks like a hand: four so-called beta-strands, corresponding to four fingers, form a beta-sheet, and an adjacent alpha-helix resembles a thumb", explains Almut Graebsch, the first author from Niessing's group. Pairs of PUR repeats bind to each other in a particular configuration that is reminiscent of a handshake, forming a functional unit. In addition to X-ray diffraction, the researchers have used a technique called small angle X-ray scattering, which revealed that the Pur-alpha protein forms dimers - two molecules of the protein bind stably to one another. This probably occurs when PUR repeats in separate molecules interact, in a similar way to the repeats within a molecule, to form the handshake structure.
Experiments in animals have shown that the symptoms of FXTAS disappear if extra Pur-alpha is supplied. "Perhaps the condition can be cured if one can find a way of stopping Pur-alpha from binding to long stretches of CGG in mRNA", says Niessing. By mutating the protein, his group has already obtained clues to how Pur-alpha binds to the CGG repeats. The next step is to find out precisely how Pur-alpha binds to RNA. This in turn could suggest ways of preventing the interactions that cause the disease. (HHZM)
Ludwig-Maximilians-Universität München
Fragile X Syndrome Current Events and Fragile X Syndrome News RSSClinical tests begin on medication to correct Fragile X defect
NIH-supported scientists at Seaside Therapeutics in Cambridge, Mass., are beginning a clinical trial of a potential medication designed to correct a central neurochemical defect underlying Fragile X syndrome, the most common inherited cause of intellectual disability.
Genetic marker linked to problem behaviors in adults with developmental disabilities
A common variation of the gene involved in regulating serotonin and norepinephrine in the brain may be linked to problem behaviors in adults with developmental and intellectual disabilities, new research indicates.
Measuring intellectual disability
Researchers from the University of California, Davis have developed a specific and quantitative means of measuring levels of the fragile X mental retardation 1 (FMR1) protein (FMRP), which is mutated in fragile X syndrome.
Small molecules might block mutant protein production in Huntington's disease
Molecules that selectively interfere with protein production can stop human cells from making the abnormal molecules that cause Huntington's disease, researchers at UT Southwestern Medical Center have found.
Melatonin is an effective treatment for sleep problems in children with autism
A study in the April 15 issue of the Journal of Clinical Sleep Medicine determined that over-the-counter melatonin medication can shorted the length of time it takes for children with autistic spectrum disorder (ASD), Fragile X Syndrome (FXS), or both to fall asleep at the beginning of the night.
Research breakthrough targets genetic diseases
A cure for debilitating genetic diseases such as Huntington's disease, Friedreich's ataxia and Fragile X syndrome is a step closer to reality, thanks to a recent scientific breakthrough.
Biologists discover link between CGG repeats in DNA and neurological disorders
Researchers have long known that some repetitive DNA sequences can make human chromosomes "fragile," i.e. appearing constricted or even broken during cell divisions.
Promising new drug being evaluated as possible treatment option for fragile X syndrome
A pilot trial of an oral drug therapy called fenobam has shown promising initial results and could be a potential new treatment option for adult patients with Fragile X syndrome (FXS).
M.I.N.D. Institute researchers call for fragile X testing throughout the lifespan
Writing in this week's Journal of the American Medical Association, UC Davis M.I.N.D. Institute researchers urge physicians to test for mutations of the fragile X gene in patients of all ages.
UCR researchers propose minocycline as a promising drug for patients with Fragile X syndrome
A UC Riverside-led team of biomedical scientists has found that a readily available drug called minocycline, used widely to treat acne and skin infections, can be used to treat Fragile X syndrome, the most common inherited cause of mental impairment and the most common cause of autism.
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