Research Roundup updates as of April 2009
Items in this article report on: causes of ALS, protective factors, familial ALS, sexuality survey, new book about ALS care
Researchers probe protective strategies
The idea that ALS may result from not just one, but a combination of factors, such as genetic variations and environmental exposures, is not new. But scientists now are beginning to home in on a number of specific protective factors, some of which have the potential to be exploited for therapeutic development.
Scientists study ‘protein stability’ factors
Several genetic mutations have been identified as causative for ALS, and several more have been implicated as risk factors for the disease (see ALSN Research Roundup, April 2009). In addition, some environmental exposures, such as the Gulf War of 1990-1991, are suspected of having combined with genetic predispositions to cause ALS.
And an increasing body of knowledge suggests that a network of biochemical interactions that maintain what scientists call “proteostasis,” or protein stability, may play a large role in protecting us from certain diseases, including ALS, and perhaps from the ravages of aging in general.
Proteostasis refers to controlling the concentration, shape and location of the body’s thousands of cellular proteins, as well as determining the proteins and other compounds with which a given protein interacts. This network kicks in when conditions inside or outside cells worsen, but its resources are limited.
Protein misfolding and clumping (aggregation), indicating a relative failure of proteostasis, have been seen in ALS-affected nerve cells, especially when the disease is caused by mutations in the SOD1 gene, as in one form of familial ALS.
Now, scientists at Northwestern University in Evanston, Ill., coordinated by Richard Morimoto, have conducted a series of experiments showing that seemingly minor variations in proteostasis can markedly affect the health of cells harboring a known ALS-causing mutation.
When these scientists introduced genes containing three distinct SOD1 mutations, all of which can cause ALS, into worms with normal proteostasis, they saw only mild cellular toxicity.
However, when genes with SOD1 mutations were expressed in worms in which proteostasis was mildly abnormal, their toxicity was markedly enhanced.
Regulators of proteostasis, the researchers say, could be developed as therapeutic agents. To support this idea, they caused a proteostasis regulator called HSF1 to be overexpressed in cells with abnormally folded SOD1 protein (from an SOD1 gene mutation) and found the cells did not develop the hallmarks of ALS that would have been expected.
Heather Durham, who has MDA support for ALS research at the Montreal Neurological Institute of McGill University, is studying whether enhancing pathways involved in maintaining proteostasis can prevent various abnormalities in ALS-affected cells.
’Alternative splicing’ lowered risk of ALS in a Canadian family
Researchers in the United States, Canada and the United Kingdom have identified a multigenerational Canadian family of Filipino descent in which a known cause of familial ALS — a mutation in the SOD1 gene — does not always cause the disease.
MDA-supported Janice Robertson at the University of Toronto, and colleagues, published their findings in the March 31, 2009, issue of Neurology.
The investigators analyzed DNA samples from 12 members of this family of 20, three of whom had died of ALS. One of those three had inherited a unique mutation in the gene for SOD1 from both parents; his DNA was included in the samples that were studied. DNA was unavailable for the two others who had died of the disease.
In the additional 11 for whom DNA was available, there were no cases of ALS. However, eight showed a single copy of the SOD1 mutation, which normally is enough to cause the disease. (All 11 were older than 48 years, including four who were older than the expected age of onset of ALS.)
This particular SOD1 gene mutation, the authors determined, is in a section of the SOD1 gene called exon 2, and it prompts an effect called “alternative splicing,” which allows cells some leeway in interpreting genetic instructions. The result in this case is reduced expression of the mutant SOD1 protein, which in turn results in fewer cases of the disease.
Therapies based on the promotion of alternative splicing may provide yet another way to reduce levels of abnormal and toxic SOD1 protein and perhaps other toxic proteins, and protect ALS-affected cells.
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Help needed with survey on sexuality in ALS
Investigators at San Francisco State University have developed an online survey to learn more about sexuality in people with ALS and their partners. You do not have to currently be with a partner to participate in this anonymous, Web-based study.
Those with ALS who want to participate must be 18 to 80 years old and have a probable or definite ALS diagnosis. Partners also must be 18 to 80, have been in a relationship with someone with ALS since before symptoms began or diagnosis was received, and must be providing at least an hour a week of help or care for the person with ALS.
Go to the ALS Survey, or contact Carisa Bielecki at firstname.lastname@example.org or Ryan Howell at email@example.com for more information.
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Latest edition of ALS guide released
Amyotrophic Lateral Sclerosis: A Guide for Patients and Families, edited by Hiroshi Mitsumoto. 3rd ed., can be purchased from Amazon.
This comprehensive volume, now in its third revision, contains everything you could possibly want to know about ALS. In its 455 pages, plus a user-friendly index, you’ll find new information on treating ALS symptoms and on noninvasive ventilation, American Academy of Neurology care guidelines, and the use of riluzole (Rilutek).
There are chapters on managing nutrition, communication, hospice care, financial realities and more. The book is edited by Hiroshi Mitsumoto, an MDA research grantee and director of the Eleanor and Lou Gehrig MDA/ALS Center at Columbia University in New York, with chapters written by experts in each area.
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