Small molecule blocking cell death may be used in Parkinson’s
Blocking interaction between proteins could protect nerve cells, study finds
A small molecule that blocks the interaction between two proteins could help protect nerve cells from premature death in neurodegenerative diseases such as Parkinson’s, a study found.
Researchers at the Walter and Eliza Hall Institute (WEHI) in Australia discovered that a newly identified small molecule, WEHI-3773, prevents the protein BAX from binding to another protein, VDAC2, and reaching the mitochondria — the cell’s energy-producing structures — thereby halting the cascade that leads to cell death.
“While not the case in most cells, in neurons turning off BAX alone may be sufficient to limit cell death,” Guillaume Lessene, PhD, head of WEHI’s new medicine and advanced technologies division and the study’s co-leader, said in an institute press release.
The discovery represents a step forward in the development of disease-modifying treatments that can slow or stop the progression of Parkinson’s and other neurodegenerative conditions that have limited or no treatment options, the researchers said.
The study, “Differential regulation of BAX and BAK apoptotic activity revealed by small molecules,” was published in Science Advances.
Small molecules could be ‘valuable tools’
“Small molecules acting like WEHI-3773 would be valuable tools to examine the [cell-protective] effects of acute BAX inhibition under neurodegenerative conditions,” the researchers wrote.
Problems with apoptosis — the process by which cells die naturally when they are damaged or no longer needed — can lead to diseases like Parkinson’s. Two key proteins involved in this mechanism are BAK and BAX. On the mitochondria, the VDAC2 protein controls both BAK and BAX by either blocking or helping their activity.
Understanding how these proteins work could help in developing treatments for Parkinson’s, a condition in which the death of dopaminergic neurons leads to progressively worse motor symptoms. Dopaminergic neurons are nerve cells that produce dopamine, a chemical involved in motor control.
“Currently there are no treatments that prevent neurons from dying to slow the progression of Parkinson’s,” said study co-leader Grant Dewson, PhD, head of the WEHI Parkinson’s Disease Research Center. “Any drugs that could be able to do this could be game changing,”
The researchers focused on BAX. When activated, this protein moves to the mitochondria and causes them to release substances that lead to cell death.
In collaboration with the National Drug Discovery Center, headquartered at WEHI, the researchers identified one out of more than 100,000 small molecules that could effectively prevent cells from dying by blocking BAX from reaching the mitochondria.
“For the first time we could keep BAX away from mitochondria and keep cells alive using this molecule,” said Kaiming Li, a researcher in Dewson’s lab and the study’s first author. “This could pave the way for next-generation cell death inhibitors to combat degenerative conditions.”
WEHI-3773 changed how VDAC2 interacted with BAK and BAX, blocking BAX from reaching the mitochondria. At the same time, it freed BAK from VDAC2, allowing it to trigger apoptosis more effectively when needed, in a controlled manner.
These findings may “inform how to design compounds that selectively influence BAX and BAK apoptotic activity as improved research tools or possibly therapeutics,” the researchers wrote.
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