Research Roundup updates as of June 2007:
TDP-43 protein's absence may mean SOD1 ALS is different
ALS that stems from mutations in the SOD1 gene may be biochemically different from ALS from other causes, suggests a report published in the May issue of Annals of Neurology.
Ian Mackenzie at the University of British Columbia in Vancouver, and colleagues, say the presence of a protein called TDP-43 in the nervous system appears to distinguish non-SOD1 ALS from SOD1 ALS.
The researchers studied postmortem tissue from 59 people with sporadic (noninherited) ALS; 15 people with familial (inherited) ALS and SOD1 gene mutations; 11 with familial ALS without SOD1 gene mutations; and 26 who had ALS with severe cognitive impairment (dementia).
All the samples from people with sporadic ALS, ALS with dementia, and non-SOD1 familial ALS had clusters containing TDP-43 in their nerve cells. Samples from those with SOD1-related familial ALS contained no TDP-43.
“The significance of this result is the implication that the pathological processes underlying ... degeneration in sporadic ALS are different from those associated with SOD1 mutations,” the investigators say.
Others say it’s not yet time to draw this conclusion (see “Are SOD1 Mice Good Models?” ).
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New method identifies toxic SOD1
A research team that included MDA grantee Christine Vande Velde at the Ludwig Institute in La Jolla, Calif., has announced that it has developed a method for detecting misfolded SOD1 protein molecules. Such proteins are highly toxic to nerve cells and cause ALS in mice and humans.
The group developed an antibody that acts as a molecular magnet, sticking to a surface on misfolded proteins.
The investigators, who published their findings online May 7 in Nature Medicine, say the ability to detect misfolded SOD1 might help in ALS diagnosis and in following disease progression, as well as in drug discovery efforts.
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Life satisfaction similar with and without disability
A study comparing people with severe and moderate disabilities caused by spinal cord injuries to able-bodied subjects found that overall satisfaction with life was the same in all groups and that mental health actually was better in the severely disabled group than in either of the other two groups.
Fatima de N. Abrantes-Pais at the University of Oklahoma Health Sciences Center in Oklahoma City, and colleagues, who published their findings online April 25 in Neurology, studied 16 people with paralysis in all four limbs; 14 who could use their arms and hands; and 11 able-bodied people.
Those with the worst physical impairments had the best scores on measures of overall mental health. The able-bodied and moderately disabled groups had statistically similar mental health scores, which were lower than those in the severely disabled group.
All groups scored the same on measures of depression.
The investigators propose that resilience in the face of adversity may not be the only factor explaining these results. They speculate that there may also be rearrangements of brain connections in response to paralysis and that these may influence coping ability.
Steven Albert, an epidemiologist at the University of Pittsburgh, studies decision making, coping ability and attitudes in people with ALS. He says he’s an “agnostic” on whether changes in the brain account for these findings.
Albert says that “expectation of what counts as good quality of life shifts with disease progression. Having less severe physical disability may actually be a harder challenge for mental health adjustment, since here people perceive themselves as ‘still in the game’ [of work-related and social competition] and limitations may sting more.”
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Origin of viral protein in ALS serum samples remains elusive
A study in the May 29 issue of Neurology is the third to find that a viral protein known as reverse transcriptase is found more frequently in people with ALS than in those who don’t have the disease.
Reverse transcriptase is an enzyme that retroviruses (a viral family that includes HIV) use to replicate themselves.
When Daniel MacGowan at Beth Israel Medical Center in New York, and colleagues, compared serum (the fluid portion of blood) from 23 ALS patients and 21 without ALS, they found reverse transcriptase in 56 percent in the ALS group and 19 percent in the non-ALS group. All the ALS patients tested negative for the HIV (AIDS) virus.
An earlier report, published in 2000, found that 59 percent of 56 ALS-affected study participants had evidence of reverse transcriptase in their serum, compared to 5 percent of the 58 tested without the disease. They didn’t find any known viruses, including HIV, in the serum samples.
A 2005 investigation reported reverse transcriptase activity in the serum of 47 percent of 30 ALS patients, compared to 18 percent of 28 unrelated people without the disease.
However, this research group also found the enzyme in 43 percent of 14 blood relatives of ALS patients who did not themselves have ALS, weakening somewhat the hypothesis that its presence could be related to the disease.
|Scientist Jerry De Zutter (right) at the ALS Therapy Development Institute shows Lynne and Augie Nieto, co-chairs of MDA's ALS Division, a "gene chip" used to identify genes that are switched on or off under various circumstances.
“The reason for the increased frequency [of reverse transcriptase] in ALS and its importance remains unknown,” the authors of the 2007 study write. They note that no known retrovirus has been found to explain the phenomenon, and suggest further testing to see whether reverse transcriptase enzyme activity increases as ALS progresses.
“It’s important to continue studies to understand this robust finding and its relevance to the cause and possible treatments for ALS,” said Merit Cudkowicz at Massachusetts General Hospital in Boston, who was part of the 2005 study and has received MDA funding for many ALS-related projects.
The ALS Therapy Development Institute (ALS-TDI) in Cambridge, Mass., in partnership with MDA, plans to use new technology to scan for viral and bacterial genes in blood and other tissues from ALS patients.
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