Researchers Uncover HSP90 Mechanism That May Help Explain Motor Nerve Death

Researchers Uncover HSP90 Mechanism That May Help Explain Motor Nerve Death

A new molecular mechanism that contributes to the death of some nerve cells has been discovered by a team of scientists led by researchers at Oregon State University.

The researchers found that blocking a protein called HSP90 can result in the activation of a receptor present in motor nerve cells, which will in turn trigger signals that induce cells to die.

This adds one more piece to better understanding the cellular process that contributes to the development of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders.

“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,” Alvaro Estevez, PhD, associate professor at OSU College of Science and corresponding author of the study, said in a university press release written by Steve Lundeberg.

“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,” he said.

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The study, “Highlight article: Ligand-independent activation of the P2X7 receptor by Hsp90 inhibition stimulates motor neuron apoptosis,” was published in Experimental Biology and Medicine.

ALS is characterized by the loss of nerve cells that specialize in controlling movement in the brain and the spinal cord.

The death of these cells can be triggered by a non-autonomous process that results from exacerbated activation of immune cells that reside in the central nervous system. But it is believed that motor neuron autonomous mechanisms contribute to ALS development and progression.

Working in collaboration with researchers at the Weill Cornell Medical College, University of Central Florida, and University of Alabama at Birmingham, the OSU team found that motor nerve cells are particularly sensitive to the inhibition of the chaperone protein known as HSP90.

Indeed, motor neurons collected from rats were shown to be 100-fold more sensitive to Hsp90 inhibition — induced by the anti-tumor antibiotic geldanamycin, used in chemotherapy — compared with other populations of nerve cells.

Further experiments revealed that the death process induced by HSP90’s inhibition was mediated via the activation of the P2X7 receptor and its downstream pro-death signals.

Based on these findings, the team believes that “altering the interaction between P2X7 receptor and Hsp90 (…) can induce motor neuron death.”

Additional data suggested that use of geldanamycin may have unintended effects. The researchers said it may contribute to a reduction of pro-survival signals, thus putting 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 Maria Clara Franco, PhD, assistant professor at the OSU College of Science and co-author of the study.

The researchers said the findings are an important advance toward understanding why certain cells in the nervous system are prone to breaking down and dying, as happens in patients with ALS.

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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.

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