Breakthrough ALS Research to Continue at UAMS
May 14, 2013 | The work of Mahmoud Kiaei, Ph.D., as part of a multi-institutional research team, could in the near future lead to clinical trials of new treatments for amyotrophic lateral sclerosis (ALS) patients at UAMS.
Mahmoud Kiaei, Ph.D., third from the left, shows Robert Griffin, M.D., left, Stacy Rudnicki, M.D., and John Crow, Ph.D., all of UAMS, a copy of a journal article detailing the results of ALS research in which he played a key role.
Kiaei, now an assistant professor in the UAMS College of Medicine Department of Neurobiology and Developmental Sciences, took part in the research while at Cornell University’s Weill Cornell Medical College in New York City. The findings were published in March in the Proceedings of the National Academy of Sciences.
Led by Alvaro Estevez, Ph.D., an associate professor at the University of Central Florida College of Medicine in Orlando, the research team examined what causes the nitration of cells that leads to cell death. That cell death causes inflammation, aging and the kind of neurodegeneration that occurs in ALS.
ALS, commonly known as Lou Gehrig’s disease, is a fatal degenerative disorder of the nerve cells in the brain and spinal cord that control voluntary muscle movement. ALS patients progressively lose the ability to function and care for themselves.
At Weill Medical College of Cornell University in New York City, Kiaei and a colleague were able to verify that Heat Shock Protein 90 (HSP 90) turned into the ”executioner” molecule involved in that kind of cell death. They used an antibody to HSP 90 and another antibody against nitortyrosine in tissue staining to identify them together in both human neurons and in mice.
“This was against the dogma and discovering a new way that cells can die,” Kiaei said. “It took a long time to show that if you nitrate that protein (Hsp90) in the lab and add it to the motor neurons, you will have some deteriorative effect, leading to death.”
In its healthy state without nitration, HSP 90 performs about 200 different functions in neurons.
Kiaei said before the findings, the cell-death model was that of an avalanche causing the catastrophic and widespread failure of a cell. In fact, it appears from the research that it is one nitrated protein, HSP 90, doing most of the damage — a boulder or stone instead of an avalanche.
“This means that we now have a target,” he said. “We know it’s out there, and we can go and find a way to block the nitrated Hsp90 and the process that leads to nitration of such an important protein for nerve cells.”
Kiaei hopes to soon start the next phase of the research at UAMS into that target, nitrated HSP 90, looking at how it is nitrated and under what circumstances. That knowledge will help in the search for a drug that can block it.
Kiaei hopes that laboratory research at UAMS will help identify drugs that are candidates for blocking nitrated HSP 90 that then can be used in clinical trials at the university. Funding first needs to be secured from public or private sources.
He also wants to study how heating an ALS patient’s spinal cord to warm the motor neurons might slow the process of the disease. Another protein important in nerve cell health is HSP 70. It can perform the chaperoning functions of HSP 90 but doesn’t appear to carry the same risk of nitration and cell death. Warming motor neurons greatly increases the HSP 70 much more than it does HSP 90. An abundance of HSP 70 then could take the place of and effectively block HSP 90 nitration in ALS patients. This work is ongoing research in Kiaei’s lab at UAMS.
Robert J. Griffin, Ph.D., director of the Radiation Biology Division in the Department of Radiation Oncology and associate professor in the UAMS College of Medicine, has done important research into thermal therapy and cancer and is collaborating with Kiaei on its uses with ALS patients.
“We always try to have the research bench and the patient bedside together,” Kiaei said. “What is in it for UAMS and Arkansas patients is that immediately we are going to look for this target and apply it to the patients.”