New insight into motor neuron death mechanisms could be a step toward ALS treatment

September 04, 2019

CORVALLIS, Ore. - Researchers at Oregon State University have made an important advance toward understanding why certain cells in the nervous system are prone to breaking down and dying, which is what happens in patients with ALS and other neurodegenerative disorders.

The study into the role a protein known as heat shock protein 90 plays in intracellular signaling is a key step on the way to figuring out the reason some motor neurons in the spinal cord die and some do not.

Findings, which could eventually lead to therapies to counter motor neuron death, were published in Experimental Biology and Medicine.

Neurons are cells in the nervous system that carry information to muscles, glands and other nerves. Motor neurons are large neurons in the spine and brain stem, with long axons extending outside the nervous system to contact muscles and control their movements via contraction.

Researchers led by Alvaro Estevez and Maria Clara Franco of the OSU College of Science have shown that a ubiquitous "protein chaperone," heat shock protein 90, is particularly sensitive to inhibition in motor neurons that depend for survival on "trophic factors" - small proteins that serve as helper molecules.

Trophic factors attach to docking sites on the surface of nerve cells, setting in motion processes that help keep a cell alive. Research in animal models has shown trophic factors may have the ability to salvage dying neurons.

"It is well known that there are some motor neuron subpopulations resistant to degeneration in ALS, and other subpopulations that are highly susceptible to degeneration," said Estevez, associate professor of biochemistry and biophysics and the corresponding author on this research. "Understanding the mechanisms involved in these different predispositions could provide new insight into how ALS progresses and open new alternatives for the development of novel treatments for the disease."

In this study, a motor-neuron-specific pool of heat shock protein 90, also known as Hsp90, repressed activation of a key cellular receptor and thus was shown to be critical to neuron survival; when Hsp90 was inhibited, motor neuron death was triggered.

The Hsp90 inhibitor used in this research was geldanamycin, an antitumor antibiotic used in chemotherapy. Findings suggest the drug may have the unintended consequence of decreasing motor neurons' trophic pathways and thus putting those nerve cells at risk.

"The inhibition of Hsp90 as a therapeutic approach may require the development of inhibitors that are more selective so the cancer cells are targeted and healthy motor neurons are not," said Franco, assistant professor of biochemistry and biophysics.

ALS, short for amyotrophic lateral sclerosis and also known as Lou Gehrig's disease, is caused by the deterioration and death of motor neurons in the spinal cord. It is progressive, debilitating and fatal.

ALS was first identified in the late 1800s and gained international recognition in 1939 when it was diagnosed in a mysteriously declining Gehrig, ending the Hall of Fame baseball career of the New York Yankees first baseman. Known as the Iron Horse for his durability - he hadn't missed a game in 15 seasons - Gehrig died two years later at age 37.
-end-
This study was made available online in May 2019 ahead of final publication in issue on August 1, 2019.

Joe Beckman, a distinguished professor of biochemistry and biophysics at OSU who has a long history as a leading ALS researcher, collaborated on this study, as did scientists from Cornell Medical College, the University of Central Florida, and the University of Alabama-Birmingham.

The National Institutes of Health and the ALS Association supported this research.

Oregon State University

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.