DLK Pathway May Cause Synapse Loss In brain Diseases

One specific injury pathway in neurons may cause the loss of synapses in neurodegenerative diseases, a study from University of Michigan suggests. The findings imply that activation of the injury pathway has negative consequences for synapses.

The pathway, called DLK, has received recent attention as a candidate drug target because it contributes to the deterioration of damaged neurons. The new findings further expand that interest by suggesting that inhibiting DLK may help neurons to maintain working synapses, which is more useful than simply preventing damaged neurons from dying.

The pathway, studied here in fruit flies, is similar to the pathway in the neurons of mammals and humans. The research team found a new relationship between the injury pathway and a protein in neurons called kinesin — specifically, a kinesin called Unc-104.

Unc-104 And DLK

Each nerve cell, or neuron, has a long nerve fiber – called an axon – that forms specialized sites for information exchange – called synapses – with other cells.

Many molecules work at synapses to coordinate the exchange of information. These molecules are largely made in the central part of the neuron – known as the cell body – and are then transported along the axon to the synapses.

The transport of these molecules is carried out by proteins known as molecular motors. One molecular motor, called KIF1A in humans and Unc-104 in fruit flies, is thought to be a major transporter of synaptic molecules.

Mutations that hinder this molecular motor result in neurons failing to form synapses and, instead, synaptic components accumulate in the cell body. However, it was not clear if Unc-104 does actually carry all of the components needed to assemble synapses along axons, or if it influences synapse formation in another way.

DLK function

Wnd/DLK signaling promotes synaptic defects by restraining total levels of presynaptic proteins when Unc-104’s function is reduced.
Credit: Jiaxing Li, et al.

The researchers found that the injury pathway is triggered when Unc-104 is damaged or mutated. This builds upon previous knowledge that the pathway is required for the key responses neurons make when damaged, including initiating the neuron to repair itself or die, depending on the context.

However, in their study, the researchers found that turning off the neuronal injury pathway can restore the function of these mutant synapses.

Restored Synapse Function

To study the role of the kinesin and the DLK injury pathway in the malfunction of synapses, the researchers imaged the synapses of dissected fruit fly larvae using a confocal microscope. Li also used electrophysiology to measure how well the synapses were firing.

The team found that when they shut down the injury pathway, the function of that synapse returned.

“That was really striking. It told us that the axon injury pathway was causing these major problems in synapses,”

says Catherine Collins, an associate professor of molecular, cellular, and developmental biology at the University of Michigan.

dlk pathway neurodegenerative

Researchers in Catherine Collins’ lab pin larvae for dissection under a microscope.
Credit: Michigan News

The team found that the pathway becomes activated when the Unc-104 kinesin is impaired, and that once activated, the pathway shuts down the formation of many of the synaptic proteins which are normally transported in axons.

“In the fruit fly system, we know the neuroanatomy really well. We can actually see how impairment of kinesin is affecting things in cell bodies, synapses and neurons. When we turned down the injury pathway in the kinesin mutants, we could see a huge mass of synaptic proteins accumulating in the cell body. That led us to the idea that the injury pathway turns down the levels of many synaptic proteins, leading to synapse malfunction,”

Collins says.

Therapeutic Target

Complementing this work, recent findings published in Science Translational Medicine suggest that the DLK pathway may be activated in patients with neurodegenerative diseases ALS and Alzheimer’s disease.

Restricting the pathway can also delay symptoms of these diseases in mouse models. This draws attention to the pathway as a potential therapeutic target.

But this could also hinder beneficial functions of the injury pathway, Collins says.

“When the injury pathway was knocked down in flies, the massive accumulations of proteins in cell bodies suggested to us that it functions as a stress response mechanism, to prevent unwanted build-up of proteins when axonal transport is impaired,”

she says.

Next, the researchers want to understand why the injury pathway appears specifically tuned to Unc-104 for its activation, and how the pathway reduces synaptic proteins.

Jiaxing Li, et al.
Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104
eLife 2017;6:e24271

Claire E. Le Pichon, et al.
Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease
Science Translational Medicine 16 Aug 2017: Vol. 9, Issue 403, eaag0394 DOI: 10.1126/scitranslmed.aag0394

Top Image: Nerve cords from the Drosophila larvae, analogous to the spinal cord, are stained to show a synaptic vesicle protein in white. Credit: Jiaxing Li/U. Michigan