While this summary is not exhaustive, it does include some of the most recent advances. If you would like certain news items featured, please contact the Research Department at researchgrants@alsa-national.org.

Japanese Team Confirms TDP-43 Protein Links ALS, FTD

A link between ALS and the cognitive change called frontotemporal dementia is reported to be a little known protein, TDP-43. A Japanese research team led by Tatsuro Oda, M.D., at the Tokyo Institute of Psychiatry confirmed in a report in December in Biochemical and Biophysical Research Communications the results published by University of Pennsylvania researchers earlier this year that this protein is tagged by ubiquitin and present in deposits in nerve cells and glia in both diseases.

Protein Common to Motor Neuron Diseases

Vimentin is a protein whose gene expression changes in all three motor neuron disease models in mice that Swiss researchers have examined, including the SOD1 mutant mouse. As published in September in the Journal of Neurochemistry and mentioned at the workshop on axon dynamics this month sponsored by The ALS Association, the vimentin signal may relate to nerves fighting back against damage. Vimentin expression correlated with the degree of damage to the motor neurons. Vimentin appears to be a general signal in neurodegeneration. It might serve as a therapeutic target in all of these including ALS.

ALS Mutation Impairs Damage Control

The VAPB mutation present in some people with motor neuron disease alters the cellular response to damaged protein, according to Japanese researchers publishing in October in the Journal of Biological Chemistry. The team led by Masaaki Matsuoka at Keio University in Tokyo, also showed that the mutant protein causes abnormal aggregates that interfere with the normal protein’s ability to deal with damaged protein. This is a common link to other mutations that produce ALS such as the SOD1 mutation.

New Way to Measure Motor Neurons in ALS

Seward Rutkove, M.D., and colleagues at Beth Israel Deaconess Medical Center, Boston, published details of a new approach to follow progression of disease and potentially find therapies that slow it, which is a strategy being funded by The ALS Association. As reported in November in Muscle & Nerve, the noninvasive method, electrical impedance myography, is an alternative to motor unit number estimation (MUNE) and shows how the muscle reacts to a slight electrical current.

Statistics using MUNE measurement need to be addressed to improve its use in clinical trials in ALS, according to Jeremy Shefner, M.D., Ph.D., State University of New York, Syracuse and collaborators publishing in October in Muscle & Nerve. They reached this conclusion by reviewing data collected in a prior trial of celecoxib in ALS.

MUNE can reliably predict disease onset and survival in SOD1 mutant mice, Shefner and colleagues reported in November in Muscle & Nerve.

New Evidence ties Glutamate to ALS

The mutation responsible for an inherited, early onset ALS affects the nerve cell messenger glutamate by changing how its receptor is assembled at the junction of nerve and muscle, according to investigators reporting in The Journal of Neuroscience in November. Huabin Cai, Ph.D., of the National Institute on Aging and collaborators at Johns Hopkins and the University of Virginia show that the end result could be a change in the flow of calcium ion that would make nerves more susceptible to damage from excitation. A part of a receptor for glutamate, called GluR2, mediates calcium flow across the cell membrane. Mice lacking the alsin protein do not put Glu2 into the receptor and cannot dampen the flow of calcium in response to excitation. This finding provides a link to many other lines of evidence implicating glutamate in ALS.

A controversy over variants in the glutamate transporter EAAT2 and ALS may be explained by a report online in October in Neurochemistry International.

Different motor neurons show a difference in a type of protein in a glutamate receptor. The difference might explain why most motor neurons die in ALS but some resist damage until the end stages.

Inflammation and ALS: TNF alpha Lacks Effect in SOD1 Mice

Canadian researchers collaborating with Jean-Pierre Julien, Ph.D., at Laval University, Quebec, published in November in the Journal of Neuroscience that the cytokine and inflammation mediator, tumor necrosis factor alpha, increased in ALS patients as well as in mice modeling the disease, does not appear to contribute to the disease course. SOD1 mutant mice were bred to mice lacking the cytokine, and the resulting double mutants lived just as long as mice with just the SOD1 mutation. Motor neuron counts also did not differ.

… but IL4 and Microglia Provide Possible ALS Target

Stanley Appel, M.D., and collaborators at Methodist Hospital, Houston, reported in November in the Journal of Neurochemistry that the inflammation mediator, interleukin-4 (IL-4) , makes microglia release other modulators but that release depends on whether the microglia are sensing and reacting to inflammation. The findings suggest a target for intervention in ALS might be IL-4 or other inflammation signals.

Another of the inflammatory cytokines, IL-13, was implicated by Japanese researchers who found elevated levels of this molecule in ALS patients, as reported in the Journal of Neuroimmunology.

Glial Cells Lose Potassium Channels in ALS Mice

The glial cells of SOD1 mutant mice lose the ability to buffer against increased potassium surrounding the cells, which results from excess excitation that is believed to occur in ALS. The findings by German researchers at the Georg-August University in Gottingen, led by Clemens Neusch, M.D., were published in November in the Journal of Neurochemistry.

Mice Can Muster Stem Cells After Cord Injected Trophic Factors

Japanese researchers found that neural precursor cells present in SOD1 mutant mice respond to helper molecules EGF and FGF2, proliferating and migrating to the ventral horn of the spinal cord where cells die in ALS. The cells become neurons rather than glia. The researchers have not yet determined if any functional recovery is possible. The report in October in the Journal of Neuroscience Research was published by investigators working with Koji Abe, M.D., Ph.D., at Okayama University.

Trophic Factor Construct Improves Delivery

Hitching the trophic or helper factor GDNF to a tetanus toxin improves delivery of this helper molecule to spinal cord nerve cells, according to a publication in November in Brain Research by Columbia University investigators collaborating with Robert Brown, M.D., D.Phil., at Massachusetts General Hospital in Boston.

Over production of GDNF in muscle but not in astrocytes extends lifespan in SOD1 mice according to a report in Experimental Neurology in October by Alexander Parsadanian, Ph.D., and collaborators at Washington University, St. Louis.

Nogo Detrimental in SOD1 Mouse

In ongoing efforts to resolve a role for the nerve repair inhibitor called Nogo, recent findings show Nogo A expressed at more than normal amounts exacerbates the retraction of the motor nerve fibers from muscle, while removing this protein lengthens life and sustains nerve connections in the SOD1 mutant mouse, according to results published in

November by French researchers collaborating with Jean-Philippe Loeffler, Ph.D., at the Louis Pasteur University, Strasbourg, France. The paper is in EMBO Reports.

Cell Transport, Calcium Binding Proteins in SOD1 Mice

Japanese researchers publish in Acta Neuropathologica in December on a potential role for cell transport in SOD1 mice. Proteins involved in moving materials from the nucleus to the cytoplasm are differentially expressed in these mice.

Changes appear in calcium binding proteins in the neurons that die compared to those that resist the SOD1 mutation, reported Hungarian investigators publishing in November in the Journal of Comparative Neurology.

For more insight into the transport processes within neurons, please see the recent workshop on axon dynamics, sponsored by The ALS Association.

Heat Shock Protein Protective in Challenged Cells

Compounds that act through the proteins involved in cellular responses to stress, called heat shock proteins, protect against mutant SOD1 in cells growing in lab dishes. Some of the drugs cross the blood brain barrier. The findings were published in Neurobiology of Disease by Heather Durham, Ph.D., of McGill University, Montreal, and collaborators.

Screening in Cells Could Yield Candidate Compounds

An effort funded by The ALS Association has made progress in finding candidates for therapeutic development in the disease, as published by Wendy Broom, Ph.D., and Robert Brown, M.D., D.Phil., and collaborators at Massachusetts General Hospital in Boston. As reported in October in the Journal of Biomolecular Screening, the approach found many compounds effective but potentially toxic. However, certain more promising leads are being pursued and funded by The ALS Association.

Aggregated Protein and ALS

Insoluble SOD1 aggregates are tagged by the marker molecule ubiquitin in mouse model of ALS, and Bunina bodies of ALS patients contain transferrin as well as cystatin C.

The trash disposal system called the proteasome, which handles such damaged proteins, is implicated in ALS with more evidence provided by a group of investigators in Finland.

The group had presented these findings at the Neuroscience meeting in Atlanta, showing that pyrrolidine dithiocarbamate decreases survival in a rat model of amyotrophic lateral sclerosis by inhibition of proteasome function. Japanese researchers publishing in the Journal of Biological Chemistry provide evidence for various different disposal routes for the mutant, aggregated SOD1 protein.

Brain Computer Interface Progress

A paralyzed person with advanced ALS was able to learn to surf the Internet solely by means of brain signals, according to a report published in Neurorehabilitation and Neural Repair in December by Niels Birbaumer, Ph.D., and colleagues at the University of Tubingen, Germany.

http://www.catfishchapter.org/news/Nov06.html