ALSA Monthly Journal News Recap for August 2005
Roberta Friedman, PhD, ALSA Research Department Information Coordinator
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
Proteins Altered in ALS Mice
A team including ALSA funded researcher Kenneth Hensley, Ph.D., at the University of Kentucky have published findings that certain proteins are changed in mice that make the mutant human enzyme, copper-zinc superoxide dismutase (SOD1). The mice show changes in the SOD1 protein itself, and in two or three other proteins including ubiquitin, which helps mark damaged proteins, and a chaperone that usually helps with proper folding of proteins inside cells. This latter protein, ??-crystallin, is also a target of investigation by others funded by ALSA. All of the altered proteins are found in abnormal deposits inside neurons in mutant mice that model ALS. The damage in ALS may be due to both accumulation of potentially harmful proteins, and also to the toxic action of these proteins to damage other proteins.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16043017&query_hl=2
Animal Study Paves Way to Clinical Testing of ALS Candidate Treatment
The encouraging animal studies that have led to clinical testing of a new candidate treatment for ALS are reported in the August Annals of Neurology, by ALS researcher Flint Beal, M.D., at the Weill Cornell medical college in New York City, and collaborators. The candidate treatment, called AEOL 10150, prolonged the survival of mice with the mutation in the protein, copper-zinc superoxide dismutase (SOD1) that is responsible for some inherited cases of ALS. The treated mice, whose symptoms are quite similar to those of ALS patients, lived about three times as long after symptom onset as mice not treated with the candidate therapy. The treated mice also showed more motor neurons surviving compared to untreated mice. Treatment was started at symptom onset for the mice to best approximate the situation for most patients who are diagnosed only when symptoms are quite apparent.
The company that makes the drug, Aeolus, said that a multiple dose safety study should be started and completed by year’s end in ALS patients. A Phase I study has found a wide range of doses that appear safe in people with ALS.
Cognitive Change Apparent in Half of ALS Patients
ALS researcher Stanley Appel and colleagues at Baylor in Houston published in the August issue of Neurology that half of patients with ALS seen at their clinic show evidence on cognitive tests that they have difficulty with mental tasks. Many had only mild changes, but for 20% of patients their problems were severe enough to merit a diagnosis of dementia. Of the series of 129 patients seen at the Baylor clinic for ALS diagnosis and treatment, only two had testing results that indicated they had Alzheimer’s disease. The others of the 20% with cognitive change had a different dementia that is characteristic of damage to the frontal and temporal lobes of the brain. Other researchers have linked this frontotemporal dementia with ALS. ALSA helped convene a conference earlier this year to discuss how to best recognize the dementia and how to help patients and families cope (see ).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=16116120&dopt=Abstract).
Role for Orderly Death of Neurons in ALS
Researchers are considering the role in ALS of the orderly process of cell death called apoptosis. This is a normal process where damaged cells are removed in a controlled manner without involving the immune system, in contrast to necrosis which activates white cells and produces inflammation. Abundant evidence of apoptosis in ALS exists but some findings have failed to confirm details of how to best interrupt the process, as published in a review article in the August Lancet Neurology. Authors Pamela Shaw, M.D., of the University of Sheffield in Britain, and colleagues, note that some drugs in clinical testing for ALS may be acting on apoptosis. But the authors suggest that the most promise is for a combination of therapies aimed at both apoptosis and other aspects of the disease process in ALS.
Molecules Designed to Bring Therapeutics to Motor Neurons
ALSA funded researcher Nicholas Boulis, M.D. of the Cleveland Clinic and colleagues published findings in lab-grown cells in the August issue of Muscle and Nerve that support the notion that preventing programmed cell death may help in ALS. They disarmed a virus and programmed it to deliver a gene for a protein that shuts off apoptosis. Once the gene was delivered to and operating within lab-grown cells, more of these nerve cells could survive exposure to excess glutamate, an excitatory messenger molecule that may over stimulate nerve cells in ALS.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16116646&query_hl=1
The Boulis team also has devised a homing molecule that specifically recognizes certain types of nerve cells including motor neurons. In research published in the August issue of Neurobiology of Disease, they describe the new molecule that may be able to bring therapeutic agents specifically to neurons to help treat ALS and other neurological disorders. The team will attempt to use such targeting molecules to improve the delivery of therapeutics that otherwise have difficulty reaching the motor neurons that die in ALS. These techniques will lay groundwork for trophic factor and gene therapies for the disease. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16023583&query_hl=4
Huntington’s Disease in Flies Treated by Antibodies
Antibodies that recognize incorrectly folded protein in a fly model of Huntington’s disease can increase the lifespan of the flies, according to a report online August 9 in the Proceedings of the National Academy of Sciences. Many neurological disorders are thought to involve proteins that cannot maintain proper structure. Antibodies expressed within cells that specifically recognize the mistaken structure can help the cell get rid of the poorly formed protein. In the flies that express the mutant protein that causes Huntington’s disease, antibodies made inside cells directed to that protein can help the flies survive: 75% of treated flies survived to adulthood, compared to only 23% of untreated flies expressing mutant huntingtin. The antibody also slowed formation of aggregates of the protein, as seen under the microscope. The researchers concluded that the approach offers a promising route for drug development.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=16061794&dopt=Abstract
Cell Dynamics Altered in ALS Mouse Neurons
Japanese researchers report changes in the mitochondria and in axon transport inside motor neurons from mice with the mutation responsible for some inherited cases of ALS. As published in the July 2005 Acta Neuropathologica, the researchers looked at neurons from the mice both before and after they developed symptoms. Using an electron microscope to compare normal mice and mutant mice, they saw increased numbers of rounded mitochondria for the mutants, and also a buildup of protein in the initial portion of the axon where this long process exits the cell to carry messages to muscle. The cell body did not show any changes, suggesting that the disease may alter transport of materials up and down the axon. ALSA funded researchers are investigating the role of mitochondria and axon dynamics in ALS.