Closing in on the Side Effects: Professor Discovers New Gene
Published on 18 July 2016
Vincristine and paclitaxel (taxol) are common chemotherapies that are effective in stopping cell division, but not without damaging nearby neurons. Martha Bhattacharya, Ph.D., assistant professor of biology, is researching the degeneration of neurons exposed to drugs like taxol and vincristine. Through a genetic screen performed by Bhattacharya and her collaborators at Washington University School of Medicine (WUSM) in St. Louis, Bhattacharya has discovered a gene, TMEM184b, which exhibits neuroprotective and neurodegenerative roles when deleted from an organism.
The results from Bhattacharya and her collaborators were published online in the April 27, 2016 issue of the Journal of Neuroscience.
When Bhattacharya began her research in 2008, she knew the applications for neuron degeneration research were vast. She describes how input from specialists was key in deciding what direction to take with her findings. “During my post-doctoral research at Washington University, I would often talk to a colleague who is a pediatric oncologist,” Bhattacharya explained. “I needed his input on what direction would have the biggest impact on patients.”
Tracing the Pathway Backwards
To model the process of nerve damage after chemotherapy treatment, Bhattacharya treated fruit flies with taxol and studied the degeneration of axons in their peripheral nervous system after they were treated. Studying the effects of this treatment in fruit flies allowed Bhattacharya to see these processes occurring in the context of the whole organism, as opposed to putting cells in a culture dish.
“I had the axons labeled with fluorescent protein so I could look at them as they started to fragment, swell and be lost,” Bhattacharya noted. Focusing on the self-destruction process that occurs in the axon after taxol exposure may lead to the identification of a drug target that could be used in patients to block nerve degeneration. This degeneration can cause chemotherapy patients to feel pain or experience thinking and memory difficulties commonly referred to as ‘chemo brain.’
Bhattacharya’s collaborators in the labs of Aaron DiAntonio, M.D., Ph.D., and Jeffrey Milbrandt, M.D., Ph.D., at WUSM found that once axon injury was induced, neurons in a dish appeared to experience no change for the first three to five hours, but at hour five or six “everything goes haywire,” Bhattacharya explained. “Signals are transmitted in the neuron in that first couple of hours. If you cut the axon, you will see a change in certain molecules in 10 minutes. But, you don’t see changes occur if you’re looking at the axon as a whole for almost six hours.”
To ensure that the function of TMEM184b was conserved in mammals, Bhattacharya used a mouse in which the TMEM184b gene was deleted. She discovered that mice without TMEM184b preserve their axons longer after injury. However, Bhattacharya and her collaborators also discovered that uninjured mutant mice experience anatomical and functional impairments in the peripheral nervous system, suggesting TMEM184b is critical for the maintenance of synaptic architecture.
Window of Opportunity
The window of time to inhibit axon injury in a patient is not yet clear to Bhattacharya and her collaborators. “In terms of treating any of these situations where axon degeneration happens, chemotherapy treatment is the simplest and easiest one to deal with because you’re not trying to intervene in a neurodegenerative disorder where severe damage has already occurred by the time the patient is diagnosed,” Bhattacharya said. “The patient knows when they’re going to start taking this treatment that is going to be toxic. They also know when they are going to stop taking it. Trying to protect neurons during chemotherapy treatment is the first application of anything that comes out of the discovery work.”
As the list of genes key to axon degeneration is refined by Bhattacharya and her collaborators, it is critical to understand how these genes are connected. “We anticipate a connection between these genes because they are involved in the same process,” Bhattacharya explained. “It is a matter of discovering those connections to better understand how to inhibit the degeneration process.”
The first author of Journal of Neuroscience paper titled, “TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance,” is Martha R. C. Bhattacharya. Coauthors include Stefanie Geisler, Sara K. Pittman, Ryan A. Doan, Conrad C. Weihl, Jeffrey Milbrandt and Aaron DiAntonio from WUSM.