The latest news on ALS Research
Expanded ataxin 2 genes increase ALS risk
Scientists working in the United States and Germany have uncovered what appears to be the most common genetic contributor to ALS so far identified. The genetic factor is a segment of the ataxin 2 gene that’s slightly longer than average, which causes the ataxin 2 protein to contain more molecules of the amino acid glutamine than it normally would.
This “polyglutamine repeat” expansion (“polyQ” expansion) seems to cause the ataxin 2 protein to last longer than usual in cells and to interact in a toxic way with another protein, TDP43, which is already known to play a role in ALS.
The researchers say that the identification of toxic interactions between ataxin 2 and TDP43 protein molecules gives scientists a new target at which to aim experimental treatments.
|Expanded ataxin 2 genes lead to expanded ataxin 2 proteins, which seem to last too long in cells and apprently lead at least one other protein astray.
Nancy Bonini and Aaron Gitler, both at the University of Pennsylvania in Philadelphia, coordinated the study team, which published its findings Aug. 26, 2010, in the journal Nature.
The normal number of glutamine molecules in an ataxin 2 protein is typically 22 or 23. An expansion to more than 34 glutamines in this protein can cause a neurological disease known as spinocerebellar ataxia type 2 (SCA2).
After a series of laboratory observations, the researchers on the current study speculated that intermediate-range glutamine expansions — perhaps those between 24 and 34, which is longer than normal but shorter than the threshold for SCA2 — could be associated with the development of ALS.
They then studied DNA from 915 people with ALS, without regard to whether or not there was a family history of the disease, and 980 people with no neurologic disease. Among those with ALS, 43 (4.7 percent) had ataxin 2 gene expansions that resulted in ataxin 2 protein molecules containing between 27 and 33 glutamines. Among those without ALS, only 14 (1.4 percent) had such expansions.
The difference means that these intermediate-length expansions “are significantly associated with increased risk for ALS,” the researchers say.
The researchers then conducted experiments that showed that ataxin 2 protein molecules with longer-than-normal polyQ tracts have a longer life span in cells than ataxin 2 molecules with shorter polyQ tracts and that they interact with TDP43 protein molecules in a toxic way.
Normally, TDP43 is found in the cell nucleus, and ataxin 2 is dispersed throughout the cytoplasm, the area of the cell outside the nucleus. However, in cells containing ataxin 2 with glutamine expansions, TDP43 was significantly more likely to be in the cytoplasm.
The researchers say they believe longer-than-normal ataxin 2 protein molecules may make TDP43 protein molecules more likely to move from the nucleus to the cytoplasm under stress conditions. TDP43 protein that’s outside the nucleus and in clumps has previously been shown to be a factor in ALS, whether or not there are mutations in the TDP43 gene.
Interfering with the interaction between ataxin 2 and TDP43 could become a new therapeutic goal in ALS. Since the ataxin 2 expansion was found in nearly 5 percent of 915 patients who had ALS due to a variety of unspecified causes, this therapeutic avenue has the potential to be beneficial to a relatively large number of people with the disease.
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More FUS-related ALS cases found
Mutations in the gene for a protein called FUS may be a more widely distributed cause of ALS than previously recognized, according to three separate reports, all published in July 2010 in the journal Neurology.
|ALS-causing FUS mutations have been identified in people from a wide variety of ethnic backgrounds.
The new results suggest mutations in the FUS gene, which plays a role in processing and transporting genetic information, may contribute to familial ALS (FALS) around the world. (The most common cause of FALS is any one of a large number of mutations in the gene for the SOD1 protein. However, 90 to 95 percent of ALS cases are not familial.) The findings give scientists additional insights into the variety of factors that can contribute to the ALS disease process.
The new reports have found ALS-causing FUS mutations in U.S. FALS patients from a variety of ethnic backgrounds, as well as in patients with a juvenile-onset form of ALS in the United Kingdom, and people with FALS in Germany. The juvenile-onset ALS patients did not have a family history of the disease.
A group coordinated by Teepu Siddique at Northwestern University in Chicago found 17 FUS mutations in 22 U.S. families affected by FALS, two families affected by FALS with dementia (severe cognitive impairment), and one with FALS with Parkinson’s disease and dementia.
The mutations were found in Americans of European origin, African-Americans, Latin Americans, and patients whose families came from China, Korea and Cambodia. “Although this study is not a population study, it suggests that FUS mutations may be a globally distributed genetic cause of FALS in patients of different genetic backgrounds,” the researchers note in their paper, published online July 28, 2010, in Neurology.
Although MDA didn’t fund this study, two directors of MDA/ALS centers were part of the research team. Benjamin Brooks, who directs the MDA/ALS Center at Carolinas Medical Center in Charlotte, N.C., and W. King Engel, who directs the MDA/ALS Center at Good Samaritan Hospital in Los Angeles, were among the investigators.
Albert Ludolph at the University of Ulm in Germany coordinated researchers at his institution, at University Hospital of Zurich in Switzerland, and at Humboldt University in Berlin. This group, which published its findings online July 21, 2010, in Neurology, studied 133 German patients with nonfamilial (“sporadic”) ALS and 58 with FALS that was not due to SOD1 mutations. They identified two FUS mutations in four German FALS families but no FUS mutations in the 133 sporadic ALS patients.
Olaf Ansorge at John Radcliffe Hospital in Oxford, United Kingdom, with colleagues at the University of Oxford and several other U.K. institutions, described their FUS findings online July 28, 2010, in Neurology.
This group conducted DNA analyses of three patients with juvenile-onset ALS whose disease symptoms began between ages 17 and 22. None had a family history of the disease. Two of the patients were found to have the same mutation in the FUS gene, and the third had a different FUS gene mutation. All three patients had abnormal clumps containing FUS protein in their nerve cells.
FUS protein molecules and molecules of another protein, TDP43, have previously been found in clumps in ALS-affected cells and apparently are not always accompanied by mutations in the genes for these proteins.
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FUS protein found in ‘stress granules’
Lawrence Hayward and Daryl Bosco at the University of Massachusetts Medical School in Worcester coordinated a team that published additional findings about the FUS protein in ALS online Aug. 10, 2010, in Human Molecular Genetics. Their findings describe how mutated FUS proteins that cause ALS form “stress granules” (which indicate that a cell is under stress) outside the cell nucleus in motor neurons. It remains to be determined whether FUS-associated stress granules are linked to the formation of toxic clumps that occur in cells in end-stage ALS, or whether they are simply markers of altered cellular function that are not toxic in and of themselves.
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Chromosome 9 DNA variants associated with SALS
Variant sequences of DNA within a small region of chromosome 9 have been found to be associated with sporadic ALS (ALS without a family history) in a study that compared samples from people with and without the disease living in the United Kingdom, United States, Netherlands, Ireland, Italy, France, Sweden and Belgium; and in another study that compared DNA samples from those with familial ALS (ALS with a family history) to those without the disease in Finland. Ammar Al-Chalabi at King’s College London coordinated the first research group, and Bryan Traynor at the National Institutes of Health in Bethesda, Md., coordinated the second. Both teams published their findings online Aug. 31, 2010, in Lancet Neurology.
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Some SOD1 abnormalities disrupt mitochondria
At least some of the many ALS-causing mutations in the SOD1 gene appear to interfere with the energy-producing activities of mitochondria in nerve cells. The mutations the researchers tested, which cause SOD1 proteins to misfold, apparently also cause them to stick to a channel on the surface of nerve-cell mitochondria and disrupt the ability of the mitochondria to import needed substances for energy production. The findings could suggest new therapeutic strategies for SOD1-related ALS. Don Cleveland, who has an MDA grant to study mitochondrial dysfunction in ALS but who was not MDA-supported on this particular study, led the research team, which published its findings Aug. 26, 2010, in Neuron.
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Neuroprotective drug development to continue
Biogen Idec and Knopp Neurosciences announced Aug. 18, 2010, that they have entered into an agreement to continue developing KNS-760704 (dexpramipexole) as an experimental treatment for ALS. The drug helps protect nerve cells under adverse conditions. A phase 2 trial by Knopp showed the drug had favorable effects on motor function and survival in people with ALS. KNS-760704 has received Orphan Drug and Fast Track designations from the U.S. Food and Drug Administration (FDA).
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Diaphragm pacing system may receive FDA approval for some with ALS
|The NeuRx diaphragm pacing system stimulates the diaphragm to contract and descend, allowing air to flow into the lungs.
The Synapse Biomedical NeuRx Diaphragm Pacing System (DPS), a device that stimulates the respiratory diaphragm with electrical signals, has received Humanitarian Use Device (HUD) designation from the U.S. Food and Drug Administration (FDA) for people with ALS who have a “stimulatable” diaphragm and are experiencing chronic breathing problems. Synapse Biomedical announced the HUD approval Oct. 8, 2010.
NeuRx Diaphragm Pacing System electrodes are surgically implanted in those with stimulatable diaphragms, meaning the individual has some preservation of the diaphragm muscle and the nerves that normally stimulate it. Once implanted, the device causes rhythmic contractions of the diaphragm that mimic natural breathing.
According to Synapse, the system is designed to exercise the diaphragm muscle not only to supplement the patient’s breathing ability but to delay diaphragm atrophy (shrinkage) and the need for invasive (tracheostomy-delivered) positive-pressure ventilation. The device can be used in conjunction with noninvasive positive-pressure ventilation, such as a BiPAP.
Clinical trials in people with ALS have suggested that the system is well-tolerated and that it may slow the decline of respiratory function.
The HUD designation establishes that the NeuRx DPS is a medical device intended to benefit people with a condition that affects fewer than 4,000 people in the United States per year. (ALS affects greater numbers than that, but only a fraction of those have stimulatable diaphragms.) Receiving a HUD designation is a first step toward possible FDA Humanitarian Designation Exemption (HDE), which allows a company to market a device to a specific population and make insurance coverage more likely.
For more information, see the Synapse Biomedical website, or contact nurse practitioner Mary Jo Elmo at University Hospitals of Cleveland at (216) 844-8594 or email@example.com.
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