Axonal HDAC1 Helps Mediate Programmed Neuron Death

The enzyme HDAC1 (histone deacetylase 1 ), normally found in the nucleus of cells, is also present in the axons of some neurons, Vanderbilt University researchers have shown. Neurons undergo programmed cell death during development if they do not nutrients, triggering a retrograde degenerative signal. The exact mechanism behind this signalling is not yet clearly understood.

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

“Some of our neurons, if their cell bodies were the size of basketballs, their axons would reach about 6 miles. 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,”

she said.

Retrograde Degenerative Signaling

Amrita Pathak, working with Bruce D. Carter, biochemistry professor and associate director of the Vanderbilt Brain Institute, along with Deyu Li, professor of mechanical engineering, developed microfluidic devices that separate the axon from the cell body, allowing them to determine which part of the degenerative signaling process was happening where.

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

enzyme HDAC1

The enzyme HDAC1 aids assembly of a molecular motor that sends a degenerative signal to a neuron’s cell body.
Credit: Carter Laboratory/Vanderbilt University

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 work was supported by grants from the Knights Templar Eye Foundation, and from the NIH.

Amrita Pathak, Emily M. Stanley, F. Edward Hickman, Natalie Wallace, Bryson Brewer, Deyu Li, Shani Gluska, Eran Perlson, Sabine Fuhrmann, Katerina Akassoglou, Francisca Bronfman, Patrizia Casaccia, Dylan T. Burnette, Bruce D. Carter
Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150Glued Deacetylation by Axonal HDAC1
Developmental Cell Volume 46, Issue 3, P376-387.E7, Aug 06, 2018

Top Image: Wellcome Images