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Enzyme helps build motor that drives neuron death

Aug. 23, 2018, 9:33 AM


Vanderbilt scientists have discovered a signaling mechanism that tells neurons to die, findings that could lead to new treatments for neurodegenerative diseases.

Amrita Pathak, PhD, a postdoctoral fellow working with Bruce Carter, PhD, professor of Biochemistry and associate director of the Vanderbilt Brain Institute, found that the enzyme histone deacetylase 1 (HDAC1), normally located in the nucleus of cells, is also present in the axons of some neurons.

Bruce Carter, PhD

When a degenerative signal is activated, HDAC1 modifies a component of a molecular motor, which then drives a signaling agent along the axon to the neuron’s cell body, killing it. The motor is integral to that process, Carter said, because of the extreme length of axons in some neurons.

“Some of our neurons, if their cell bodies were the size of basketballs, their axons would reach about 6 miles,” he said. “This is a new finding in terms of how the motor can be assembled and allow transport back to the cell body. There has been evidence of a retrograde degenerative signal, and now we’ve identified key components and a mechanism controlling their transport.”

Their findings were reported Aug. 6 in the journal Developmental Cell.

The biochemistry team worked with Deyu Li, PhD, professor of Mechanical Engineering, to build microfluidic devices that separate the nerve axon from the cell body, allowing the researchers to determine which part of the degenerative signaling process was happening where.

The Carter laboratory has long studied the p75 neurotrophin receptor and the role it plays in development and diseases of the brain. It’s implicated in Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, ischemia, hormone deficiency and other diseases or injuries to the nervous system.

Their research builds on the work of Vanderbilt University biochemist Stanley Cohen, PhD, Distinguished Professor of Biochemistry, Emeritus, who in 1986 shared the Nobel Prize for Physiology or Medicine for the discovery of nerve growth factor, the founding member of the neurotrophin family, and its effect on cells, Carter said.

Pathak, who used sympathetic neurons for her research, intends to find whether similar cellular processes are happening in motor neurons known to be affected in ALS.

“If we can block that, we can block the neuron death that occurs,” she said.

The research was supported by grants from Knights Templar Eye Foundation and from the National Institutes of Health (NS038220, NS102365, NS097976, EY024373, NS042925).

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