ALS Research Journal News - January 2007

Incidence of ALS Published in Neurology

Updated estimates of the incidence of several neurological disorders based on review of the current literature are published in Neurology by a collaboration including Deborah Hirtz, M.D., with the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. The estimates include discussion of the incidence of ALS (also known as Lou Gehrig’s Disease in the U.S.). “Current, accurate estimates of the numbers of people affected by neurological disorders are needed to understand the burden of these conditions on patients, families and society to plan and carry out research on their causes and treatment and to provide adequate services to people who suffer from these illnesses,” said Hirtz in a press statement.
http://www.ncbi.nlm.nih.gov/pubmed/17261678

A separate study carried out in Lombardy, Italy, shows the incidence there of ALS is similar to that elsewhere in the world. The report by the SLALOM group of investigators, led by Ettore Beghi, M.D., of the Mario Negri Institute in Milan, was published in January in Neurology.
http://www.ncbi.nlm.nih.gov/pubmed/17210896

Progranulin Mutation in FTD, ALS

A mutation in the gene coding for the protein, progranulin, was found in a patient with cognitive change who is from a family in which ALS is inherited in a dominant manner, as well as in two other patients with family history of cognitive change, reported investigators online in Neurology in January. Led by Jordan Grafman, Ph.D., of the National Institutes of Health, and collaborators at Indiana University and in Italy, the multinational team of investigators found that the mutation of progranulin in this particular patient produced the symptoms of frontotemporal dementia (FTD) although no definitive motor symptoms were apparent. The progranulin gene is on chromosome 17 at a different location than other mutations that also cause FTD. The progranulin gene produces proteins that may have properties of supporting growth and health of neurons.
http://www.ncbi.nlm.nih.gov/pubmed/17202431

Swallowing Affected in Some FTD Patients

An overlap with a common aspect of ALS occurs in at least some patients with frontotemporal dementia. Dysphagia, or impaired swallowing, often appears as ALS progresses and can be the presenting symptom of bulbar onset ALS, and now it seems this problem also can happen in frontotemporal dementia. A series of 21 FTD patients examined by Bruce Miller, M.D., and colleagues at the University of California, San Francisco, showed abnormalities on fiber optic endoscopic examination of swallowing in 12. Four of the patients’ caregivers had reported some problem with swallowing. The investigators concluded that the appearance of swallowing disorder in FTD marks progression of the disease progress into the brain centers that coordinate the muscles of the throat.
http://www.ncbi.nlm.nih.gov/pubmed/17210809

Iron Handling Gene Change Associated with ALS

Leonard H. Van den Berg, M.D., Ph.D., at the University Medical Center in Utrecht, and colleagues showed that variation in a gene involved in the body’s handling of iron may be associated with some instances of ALS. Other researchers have shown this gene variation is associated with ALS occurring nearly twice as often in people with ALS as in those who do not have the disease for populations studied in Ireland and in the U.K.

Investigation in the Dutch population, now published in January in the Archives of Neurology, showed similarly that people with both copies of the gene for HFE changed by the H63D mutation are twice as likely to have ALS. Those with only one copy changed, and with ALS, tended to get ALS later in life. Mutations in the Hfe gene can result in the iron overload disease called hemochromatosis. Changing iron balance in neurons can produce similar changes to the damage seen with ALS. This is an example of a gene variation that could work together with other factors to produce the disease.
http://www.ncbi.nlm.nih.gov/pubmed/17210810

Metal Proteins, Lipid Peroxides, Increase Early in SOD1 Mice

Early changes in spinal cord in metal containing proteins, in the metals copper and zinc, and in lipid by products, may be hallmarks of ALS at least in a mouse model as reported by Japanese researchers. The team led by Toyofumi Suzuki, Ph.D., at Nihon University, Chiba, published in Toxicology in January. The increases are apparent at eight weeks in the mice, long before they show any symptoms. Certain forms of the proteins, called metallothioneins, increased further as the mice developed paralysis. These proteins help handle the required metal ions for essential enzymes such as the copper, zinc superoxide dismutase (SOD1), the enzyme that is altered in some inherited forms of ALS. The investigators concluded that the changes suggest the metallothionein proteins are attempting to counter oxidative stress in the disease.
http://www.ncbi.nlm.nih.gov/pubmed/17097207

Copper ion held by the SOD1 molecule may be a key to how the enzyme is altered by some mutations that cause ALS, according to findings published by David Borchelt, Ph.D., and colleagues at Johns Hopkins University in Baltimore, Md. As reported in the Journal of Biological Chemistry in January, the copper ion may be vital to the stable pairing of the SOD1 enzyme which is its normal form. The findings are part of an effort funded by The ALS Association to manipulate internal portions of the protein to define the critical elements within SOD1 responsible for toxicity. The investigations should allow this research team to map the minimal elements within SOD1 that are required to elicit ALS.
http://www.ncbi.nlm.nih.gov/pubmed/17092942

Motor Neurons Not Adept at Calcium Buffering

Adding to evidence implicating calcium flow in ALS, the motor neurons appear to uniquely lack the calcium handling ability of other nerve cell types, according to research by British and German investigators. Publishing on line in January in Cell Calcium, Ludo Van Den Bosch, Ph.D., and collaborators at the Medical School in Hannover, and the University of Sheffield, showed in lab dishes motor neurons responding to stimulation by increased inflow of calcium that saturates the calcium buffering of mitochondria. In fact, the motor neurons had lower densities of mitochondria than other neurons. This could explain the selective vulnerability of motor neurons to the disease process in ALS suspected to impair the mitochondria.
http://www.ncbi.nlm.nih.gov/pubmed/17241659

Immunization Against SOD1 Mutant Protein Helps Mice

Immunizing mice with the SOD1 mutation using the mutant protein itself to prompt the immune system to destroy what the body is producing helps mice with the mutation survive longer according to research by Jean-Pierre Julien, Ph.D., of the University of Laval, Quebec, Canada, and colleagues. Publishing online in the Proceedings of the National Academy of Sciences in January, the Canadian team showed that vaccination before symptoms appear could prolong survival in two different SOD1 mutant bearing mice. The strategy was based on the recent findings that the SOD1 protein is secreted by cells, thus allowing the immune system to see it so that a vaccination approach might prompt a response as if the protein is foreign. Only human testing would be able to show that this strategy might work in people with the SOD1 mutation.

RNAi Prolongs Survival in SOD1 Mice

Japanese researchers published in the Archives of Neurology in January that mice with the SOD1 mutation survive longer with the disease if crossed with mice that also carry a gene to produce small interfering RNA that inhibits production of SOD1 protein. These researchers led by Hidehiro Mizusawa, M.D., Ph.D., at the Tokyo Medical and Dental University, had shown previously that the mice also have delayed onset of the disease. This is further evidence that RNAi may be a promising therapeutic approach for ALS.
http://www.ncbi.nlm.nih.gov/pubmed/16221675

VEGF Increase Delays Onset in SOD1 Mice

As reported in January in the Journal of Neuroscience, California and German researchers could prolong the survival of the SOD1 mouse by breeding with mice with a gene that produces more than the usual amount of VEGF. The double mutant mice lived about twenty days longer without symptoms but progressed as rapidly once their disease appeared. This report from the team led by David Greenberg, M.D., Ph.D., Buck Institute, Novato, and colleagues from the University of Heidelberg, adds to the evidence that this supportive molecule can protect motor neurons against the toxic action of the SOD1. Treatment strategies to boost exposure of motor neurons to VEGF are being explored.
http://www.ncbi.nlm.nih.gov/pubmed/17215390

Cannabinoid Prolongs Survival in SOD1 Mice Starting at Symptom Onset

Investigators at the University of Arkansas, Little Rock, published findings, first presented at the Society for Neuroscience meeting last fall, that a selective drug that acts at a particular cannabinoid receptor increased lifespan by a couple of weeks in SOD1 mice. The beneficial effect occurred when the drug treatment was started at symptom onset in the mice. Most likely, the cannabinoid effect is through modulation of inflammation, concluded the researchers, led by John Crow, Ph.D., and Paul Prather, Ph.D., writing in the Journal of Neuroscience in January. Other suggestive findings were reported by British investigators (see monthly journal news for May 2006) http://www.alsa.org/research/article.cfm?id=969&CFID=2&CFTOKEN=68144428), who found that SOD1 mutant mice lacking one of the natural receptors for cannabinoids on their cells did show longer life but no change of disease onset. Whether or not this class of drugs can hold promise for treatment of ALS remains to be demonstrated in a well-designed clinical trial. The ALS Association supports additional research into the potential for cannabinoids in ALS but cautions that the mix of compounds in marijuana does not have proven efficacy in the disease.
http://www.ncbi.nlm.nih.gov/pubmed/17241118

Inflammation Protein Changes in Glial Cells in SOD1 Mice

Caterina Bendotti, M.D., Ph.D., and colleagues at the Mario Negri Institute in Milan, Italy, and collaborators at the University of Palermo, show that a protein involved in inflammation changes during the disease in mice with the mutation in the SOD1 protein most clearly in glial cells. High mobility group box protein 1 (HMGB1) is a protein found in the nucleus of most cells that can activate inflammatory processes. It could provide a new target at which to aim potential therapeutics in ALS according to the findings reported in January in Neuroscience Letters.
http://www.ncbi.nlm.nih.gov/pubmed/17196331

Certain Protein Levels Altered in ALS

Italian investigators looked for changes in levels of proteins in the SOD1 mouse early in life before symptoms appear and found that altered protein amounts include those molecules with a role in mitochondrial function, the handling of abnormal deposits within cells, and the cellular response to stress. The researchers also found a change in cyclophilin A, a molecule that protects cells from oxidative stress. The team led by Valentina Bonetto at the Dulbecco Telethon Institute and colleagues at the Mario Negri Institute in Milan, Italy, published online in December in the Biochemical and

Biophysiological Research Communications.
http://www.ncbi.nlm.nih.gov/pubmed/17196550

Amniotic Fluid Sampling Proposed as Stem Cell Source

Investigators at Wake Forest University led by Anthony Atala, M.D., collaborating with Harvard and Children’s Hospital colleagues published in Nature Biotechnology in January that stem cells found in amniotic fluid samples left over from prenatal tests can generate neurons that implant and integrate into newborn mouse brain. These are cells shed by the fetus. The percent of stem cells surviving was actually enhanced by a neurodegenerative condition caused by an inherited lack of an essential enzyme in a mouse model called twitcher. This suggests an alternative source for stem cells that avoids ethical issues yet still provides a possible therapeutic approach to diseases such as ALS. Further research will need to confirm and extend the findings.
http://www.ncbi.nlm.nih.gov/pubmed/17206138

Twitcher Mice Rescued by Combined Gene Therapy and Bone Marrow Treatment

In the mouse model used by the stem cell researchers cited above, nerve cells die when an enzyme defect causes accumulation of waste fats within the storage sacs called lysozymes. This storage disorder, called Krabbe disease in people, kills mice rapidly after birth. Affected mice given a combination of a gene therapy to replace the defective gene did far better if also given a bone marrow transplant. Apparently the marrow replacement counters brain inflammation the investigators suggested. The team led by Mark Sands, Ph.D., at Washington University in St. Louis, reported in Molecular Therapy in January. ALS research has identified inflammation as an important aspect, and some attempts at bone marrow treatment suggest this might be worth investigating further in the disease, perhaps as part of a combined treatment strategy.
http://www.ncbi.nlm.nih.gov/pubmed/17164774