ALSA Monthly Journal News Recap for September 2005
From: Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator
While this summary is not exhaustive, it does include some of the most recent advances.
Gene Tied to Iron Metabolism Linked to ALS
A gene involved in handling iron in the body may be associated with some cases of sporadic ALS, according to British researchers, who have published their findings after reporting them last year at the International Symposium on ALS/MND in Philadelphia. A genetic condition where too much iron accumulates, called hemochromatosis, is due to a slight change in a gene. Many variants of a gene occur among different individuals and only sometimes produce disease or defects. ALSA-funded investigator Orla Hardiman, M.D. at Beaumont Hospital in Dublin, and Karen Morrison Ph.D., at the University of Birmingham, and colleagues report in the September issue of Neurology that a particular variant of an iron handling gene is nearly twice as likely to be present in people with sporadic ALS. Researchers have found higher levels of iron in the spinal cord of patients with ALS. Problems handling iron have been linked to oxidative stress as well. Further studies will need to confirm the association and to probe how the change might be related to ALS.
SMN Gene Variants May Influence ALS
Variants of a gene linked to an inherited, childhood onset motor neuron disorder occurs more frequently in patients with ALS than in the overall population. Leonard Van den Berg, M.D., Ph.D., at the University Medical Center, Utrecht and colleagues had previously reported a link that others failed to replicate. Now the Dutch investigators delve more into the complex genetics of spinal muscular atrophy (SMA), a disease influenced by two genes that have differing transcription patterns and copy numbers, SMN 1 and SMN2. They demonstrate that low copy numbers of both genes were significantly associated with the risk of ALS. The researchers conclude that people producing less SMN protein may be more susceptible to ALS.
Mutation in Spastin Gene in a Case of ALS
A person with sporadic ALS was found to have a mutation in the spastin gene. This man lived for quite a long time with ALS, having had the disease for 49 years at the time his gene change was found, at age 73. The German investigator Thomas Meyer, M.D., Peter Linke, M.D., and colleagues at the University Hospital in Berlin, reporting the case in the July issue of Neurology, noted that changes in the spastin gene, known to produce an inherited problem of the lower motor neurons causing spasticity, might produce a variety of motor neuron diseases including ALS.
Genetic Background Can Interact with SOD1 mutation in Mice
Mice with different genetic backgrounds can have different time to onset and lifespan when the SOD1 mutation is introduced. ALSA-funded researcher Terry Heiman-Patterson, M.D., at Drexel University in Philadelphia and colleagues report in the September issue of the Journal of Neurological Sciences that mice with the same copy number of the introduced gene, but of different genetic backgrounds (strains), can live for different amounts of time with the mutation. Similarly, humans with sporadic ALS have different times of onset and progression suggesting genetic interaction with environment. The researchers report a shortened lifespan when the G93A SOD1 gene is engineered into mice of the SJL/J background and an increased survival with the loss of gender differences in lifespan when the gene is introduced into mice of the C57BL/6J background. The findings should lead to ways to investigate how ALS might result from an individual’s genetics interacting with life experiences.
Acquired Genetic Changes Postulated for ALS
Features of sporadic ALS suggest that the disease results from changes in genes acquired over a person’s lifetime, according to a theory proposed by neurologist Carmel Armon, M.D., Baystate Medical Center, Springfield, Mass., in the September issue of Muscle and Nerve. Armon makes the case that as in cancer, acquired genetic changes in ALS might produce a disease that starts in one place in the body and spreads. Much more research will be needed to support or deny this idea about how ALS might be produced.
Proteins in Motor Neurons Altered in ALS Rats
Rats with a mutation found in some inherited ALS have changes to structural proteins that help the long process of the motor neuron, called the axon, to function properly. One of the neurofilament proteins in the ALS rats have more glycosylation, a chemical modification, compared to normal rats. This type of modification has been less studied than another modification, called phosphorylation. ALS rats in fact have more phosphorylation of the neurofilament protein. It is possible to find glycosylation in human brain after death. Further studies should be able to determine the possible role of this change in neurofilaments in ALS. The report by University of Osnabruck researcher Roland Brandt, Ph.D., and colleagues appears in the September issue of The Journal of Biological Chemistry.
Signal Molecule Stabilizes Nerve to Muscle Communication
Researchers working with flies showed that a signal molecule can help muscles and nerves stay in healthy communication. The molecule, called bone morphogenetic protein, could be a new target for drug therapies aimed at neurodegenerative diseases such as ALS. The investigators at the University of California, San Francisco, led by Graeme Davis, Ph.D., published in the September issue of the journal Neuron that bone morphogenetic protein (abbreviated as BMP) keeps the connections stable between nerves and muscles that they control. Without BMP, the nerve retracts and the muscle withers. The fruit fly enables rapid progress as its genes are easily manipulated in relatively short time. ALSA funded investigators are implementing lab models such as the fly to study how new therapeutic strategies can be applied to ALS.
Inhibitor of Heat Shock Protein Helps Mouse with Neurodegenerative Disease
Mice with a neurodegenerative disease are aided by a treatment that helps cells get rid of defective protein. The mice model the human disease, spinal and bulbar muscular atrophy (also called Kennedy’s disease), caused by a gene mutation similar to the mutation in Huntington’s disease, with a repeated sequence that extends the gene. The researchers tested an inhibitor of heat shock protein 70, called 17-AAG, already a candidate in cancers. It has no obvious toxicity in the mice treated for 20 weeks (an earlier inhibitor of this heat shock protein worked against cancers but was limited by liver toxicity). The researchers led by Gen Sobue of Nagoya University noted in their report in the September 11 online issue of Nature Medicine that other neurodegenerative diseases might respond to this treatment strategy. ALSA funded investigators are looking into the role of heat shock proteins in protecting motor neurons damaged by the disease.
Cases of ALS Increased Slightly in 1980s
A report in the journal Neuroepidemiology by researchers at the Centers for Disease Control and Prevention in Atlanta says that the number of cases of ALS slightly increased in the years 1979 to 1983 and has remained at the new rate since then. Women ages 65 and older, and young people ages 20 to 49 were responsible for the increase. The annual death rate from ALS in the U.S. has been 1.84 per 100,000 from 1979 through 1998. The investigators led by Lawrence Schonberger, MD, MPH, examined the death records from the national multiple cause-of-death database. ALS apparently occurs more frequently in the northern states. These findings should inform further investigation into the possible environmental factors associated with ALS.
A report on the rate of cases of ALS in Italy by Harvard and Italian epidemiologists in the August issue of the Journal of Neurology, Neurosurgery, and Psychiatry did not support a difference in incidence of the disease with latitude.
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