ALS Research Roundup Spring 2011

by ALSN Staff on Tue, 2011-03-01 10:47
ALS TDI is funded through Augie's Quest, MDA's aggressive cure-driven effort focused on ALS.
Article Highlights:

ALS TDI expansion among 2011 goals

Building on progress made in 2010, the MDA-supported ALS Therapy Development Institute (ALS TDI) has outlined a number of milestones it plans to meet in 2011.  

Steve Perrin, ALS TDI chief scientific officer and CEO at the nonprofit biotech in Cambridge, Mass., presented the Institute’s goals via webinar (online seminar) on Jan. 19, 2011.

One of the most exciting goals, reflective of ALS TDI’s progress, is to significantly expand the Institute’s core research facility. More space means increased capability to accelerate research toward the development of effective treatments for ALS. The expansion should enable the Institute to hire two or three additional scientists.

Also high on the list is the Institute’s plan to get its TDP43 ALS research mouse colony up and running; this includes completion of a full characterization of the new mouse, which is expected to help scientists design the best possible trials for its use in drug screening. The mouse carries a mutation in the TDP43 gene, which is associated with some cases of human ALS.

ALS TDI recently acquired an Affymetrix GeneTitan, an automated device that can monitor gene activity (also known as gene “expression”) and search for DNA mutations via a process called “genome-wide SNP genotyping.” This crucial tool will be used to generate a “pharmacogenomic” profile of multiple therapeutic agents being tested for efficacy in the SOD1 research mouse.

The addition of the GeneTitan also will serve as part of ALS TDI’s implementation of a multitherapeutic screening program that will allow researchers to study the pharmacodynamics (the way a drug behaves in the body) of candidate therapeutic agents, and global changes in biological pathways relevant to ALS.

Additionally, ALS TDI plans to screen between 25 and 30 new potential therapeutic agents for ALS in the preclinical model. Part of this process includes determining the correct dose of a drug needed to obtain a desired effect without causing unwanted or harmful side effects.

MDA supports ALS TDI as part of its focus on “translational research” to accelerate the development of viable therapies. View the complete archived webinar on ALS TDI’s website. (Note: You must register to view the webcast.)

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VCP gene implicated in familial ALS

A multinational study group has uncovered five mutations in the valosin-containing protein (VCP) gene and identified them as molecular causes of some familial forms of ALS.

The addition of the VCP gene to the growing list of genes associated with ALS provides additional evidence and another angle through which scientists can probe the underpinnings of the disease.

The research team, which published its findings online Dec. 9, 2010, in the journal Neuron, used a sophisticated new technique called “exome sequencing” to implicate a VCP gene mutation in four individuals representing four generations of an Italian family. MDA supported Michael Benatar, associate professor of neurology and epidemiology at the University of Miami, for this work.

After uncovering the first VCP mutation, the researchers examined 210 ALS-affected individuals from unrelated families, as well as samples from 1,205 unaffected individuals who made up the “control” group. They found four additional VCP mutations present in approximately 1 to 2 percent of familial ALS cases — a frequency, the researchers wrote, comparable to that of cases caused by two other known ALS-associated genes, TDP43 and FUS.

VCP performs a variety of vital functions within the cell, one of which is helping support the ubiquitination/protein degradation pathway responsible for the breakdown and disposal of malformed, nonfunctional or otherwise unwanted proteins. This natural cellular waste disposal system, called autophagy (literally “self-eating”), is a necessary function in maintaining the health of the cell.

Results from previous studies have suggested that disease-causing mutations in VCP may impair the protein’s crucial role in the cell’s natural cleanup and garbage disposal system, leading to the accumulation in neurons of protein clumps called inclusions.

It’s also been demonstrated in mouse models and in cell culture studies in the laboratory that VCP mutations affect TDP43 protein function, in part by causing the protein to move from where it normally resides in the cell’s nucleus out to the surrounding cytoplasm. TDP43 structural and functional changes also have been observed in the spinal cord motor neurons of mice with VCP mutations.

However, the molecular mechanisms by which mutations in the VCP gene cause motor neuron degeneration and the various features of VCP-mediated ALS are not yet clear.

“It is tempting to speculate that mutations in VCP are responsible for TDP43 mislocalization and that this in turn leads to neurodegeneration,” Benatar said. “But we have not yet shown this to be the case.”

However, the recognition that mutations in VCP can cause ALS provides “a unique opportunity to gain insight” into the ALS disease process, Benatar said. Also valuable is the team’s initial evidence that impairment of the cell’s protein degradation pathway is a causative factor for the disease.

Although the frequency of VCP mutations in familial ALS must be confirmed via independent testing, the study authors wrote, it appears “comparable to that reported for TDP43 and FUS mutations, highlighting the relative significance of this gene as a cause of familial ALS.”

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Blood samples stored in biobank will help ALS research

People with ALS who want to help scientists find ways to slow and stop the disease can now donate blood for use in ALS research.

You can help advance ALS research via donation of a tissue or blood sample.

Scientists at the National Institute of General Medical Sciences (NIGMS) Human Genetic Cell Repository at the Coriell Institute for Medical Research in Camden, N.J., are seeking blood samples from people with ALS and other genetic neuromuscular diseases.

Participation requires a blood or tissue sample, as well as a completed consent form, a submission form and a clinical information summary form.

Numerous measures are taken to protect the privacy and anonymity of the donor, but these measures also prevent any personal information from being derived from the sample. For this reason, the bank is unable to provide results of any kind to donors.

Rather, the anonymous samples are used by researchers around the world who use cell lines and DNA to discover new disease-causing genes; study known genes and their expression; and devise new genetic tests.

Samples from the NIGMS biobank, the world’s largest, have been used in more than 5,000 scientific publications and by scientists in more than 50 countries, the organization says.

The Coriell Institute for Medical Research mails participants a collection kit and pays for the cost of shipping the sample, but not the costs associated with collecting the blood and tissue.

Once a sample is submitted, it can’t be removed.

For more information, e-mail Tara Schmidlen at, or call (856) 757-4822. More information also may be found on the Coriell Institute's website.

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Lack of normal TDP43 function leads to nerve cell death in mice

A new study suggests that the loss of normally functioning TDP43 protein in the cell nucleus causes motor neuron degeneration and death in two diseases characterized by TDP43-containing protein clumps in the brain and spinal cord: ALS and frontotemporal lobar degeneration.

The study results are the first to pinpoint a mechanism by which mutant TDP43 causes nerve cells to die. If confirmed, the findings could lead to the development of biomarkers (biological indicators) in the two disorders, as well as new therapeutic strategies to slow or halt — or even prevent — disease onset and progression.

Virginia M.-Y. Lee, director of the Center for Neurodegenerative Disease Research at the University of Pennsylvania in Philadelphia, coordinated the research team, which published its findings online Jan. 4, 2011, in the Journal of Clinical Investigation.

The TDP43 protein performs a number of vital functions, typically inside the nucleus of the cell. Abnormal forms of the protein, however, aggregate in clumps (“inclusions”) in the cytoplasm, or outer area of the cell.

Although TDP43 has been associated with ALS since 2006, the mechanism by which it causes the death of muscle-controlling neurons remains unclear. The two major competing theories are:

  • the accumulation of TDP43-containing inclusions in the brain and spinal cord is toxic and harmful to neurons; and
  • the loss of TDP43’s normal function leaves the cell at a deficit and unable to precisely regulate further TDP43 gene activity.

To determine the effects of mislocated TDP43 on neurons, the researchers engineered a mouse model of ALS that carries mutant human TDP43 protein in the outer regions of motor neurons. They compared these mice to another model in which normal human TDP43 protein was expressed in the nucleus. In both cases, neuron loss occurred in known vulnerable regions of the brain and in part of the spinal cord tract.

Also in both cases, the insertion of human TDP43 genes in the mice, and subsequent human TDP43 protein activity (normal, or mutated) caused a dramatic loss of function associated with the elimination of normal mouse TDP43.

The findings suggest that the cell’s inability to regulate its own normal TDP43 — not TDP43-containing protein clumps — leads to motor neuron death.

One caveat: The investigators found that TDP43 inclusions were very rare in the mouse cells observed in their study. While this suggests that these inclusions may not be necessary for neurodegeneration, it’s somewhat mysterious in that such aggregates are numerous in human tissues of people with ALS.

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The nutritional supplement spirulina has shown benefits in weight maintenance and muscle function in mice with an ALS-like disease.

Nutritional supplement may be neuroprotective in ALS mice

A study of 15 mice with a genetic mutation that causes an ALS-like disease suggests that the nutritional supplement spirulina may have some protective effects on motor neurons.

Spirulina is a type of microscopic blue-green algae shaped like a spiral that lives in fresh or salt water. It’s rich in protein, fatty acids and the B vitamins (thiamine, riboflavin, nicotinamide, pyroxidine and folic acid), as well as vitamins C, D, A and E. It also is a source of minerals including high levels of potassium and lower levels of calcium, chromium, copper, iron, magnesium, manganese, phosphorous, selenium, sodium and zinc.

Eight mice received a powdered supplement of spirulina in addition to their regular food; these mice maintained their weight and a limb extension reflex in the right hind leg (but not the left) better than the seven mice on the regular diet alone.

Caveats are that the number of mice was small; the investigators started the spirulina supplement long before ALS-like symptoms began (a highly unlikely treatment approach in humans); surviving motor neuron numbers were not compared in the two diet groups; and the effect of spirulina on life span was not determined.

Note: Although spirulina is readily available in stores, talk with your ALS physician before adding any medication or nutritional supplement to your daily regimen. (For more on nutrition in ALS, see Eat, Drink and Be Healthy is the Motto in ALS.)

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Biogen Idec plans to develop antibodies to TDP43 protein

Biogen Idec, a Weston, Mass.-based biotechnology company, has purchased the rights from the Swiss company Neurimmune to develop therapies for ALS and two other neurodegenerative diseases.

Neurimmune specializes in the identification of human immune system proteins (antibodies) that can be put into a drug-discovery pipeline. Antibodies often can stop the actions of other proteins to which they’re targeted. The Neurimmune ALS program has focused on development of antibodies to the TDP43 protein, which appears to have toxic properties in this disease.

To read Biogen Idec’s press release, visit the website, click on “media,” then “press releases,” then “archived press releases.” Choose “2010,” and then click on the release, dated Dec. 20, 2010, “Biogen Idec and Neurimmune Announce Agreement on Three Neurodegenerative Disease Programs.”

Why wait? Read ALS research updates online each month.

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