Pathway in Neurons may Contribute to Neurodegenerative Disease
Credit: University of Michigan
An injury pathway in the neurons of fruit flies may cause the loss of synapses in diseases such as Alzheimer's and ALS, according to University of Michigan researchers.
This 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 U-M team, which includes former doctoral student Jiaxing Li and Catherine Collins, associate professor of molecular, cellular and developmental biology, found a new relationship between the injury pathway and a protein in neurons called kinesin—specifically, a kinesin called Unc-104.
When neurons communicate with each other, they extend a projection called an axon toward each other and form sites for information exchange called synapses. Transmitting information between synapses requires many protein molecules, which are manufactured within the neuron cell body and ferried over long distances within axons by kinesins such as Unc-104. The Unc-104 kinesin seems to carry many of the proteins needed for the neuron to release neurotransmitters for information exchange.
The U-M 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.
When Unc-104 is damaged or mutated, synapses become defective. Previously, researchers assumed that this is because of a failure to transport synaptic proteins to synapse sites. However, in their study, Li, Collins and their team found that turning off the neuronal injury pathway can restore the function of these mutant synapses. Their results are published in the journal eLife.
To study the role of the kinesin and the injury pathway in the malfunction of synapses, the researchers imaged the synapses of dissected fruit fly larvae using a confocal microscope. Working in the neighboring lab of U-M professor Richard Hume, 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 was restored.
"That was really striking," Collins said. "It told us that the axon injury pathway was causing these major problems in synapses."
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," Collins said. "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."
The findings imply that activation of the injury pathway has negative consequences for synapses. Complementing this work, recent findings published in Science Translational Medicine suggest that the injury 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 said.
This article has been republished from materials provided by University of Michigan. Note: material may have been edited for length and content. For further information, please contact the cited source.
Li, J., Zhang, Y. V., Adib, E. A., Stanchev, D. T., Xiong, X., Klinedinst, S., . . . Collins, C. A. (2017). Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104. ELife, 6. doi:10.7554/elife.24271
Multidisciplinary Study Suggests New Strategy for Drug DiscoveryNews
A joint industry/academia study of a cancer target protein reveals unusual relation between binding site flexibility and drug-target lifetime. The results, , suggest a new strategy for drug discovery.READ MORE
Concept Life Sciences appoints New Group Programme Manager and US Head of SalesNews
Key leadership appointments support integration of the Group and expansion in the US market.READ MORE
Comments | 1 ADD COMMENT
Diane Tamar | Nov 16, 2017
I have ADHD, OCD, depression, primary biliary cirrhosis (autoimmune disease) and ALS. I didn't have health care I just thought it was a stroke, but it started with my voice. When it started to get worse I went to a neurologist. and was diagonised with amyotrophic lateral sclerosis. i was able to walk with assistance nothing was really working to help my condition.I went off the riluzole (with the doctor’s knowledge) and started on amyotrophic lateral sclerosis herbal formula i ordered from Health Herbal Clinic, Just 7 weeks into the Herbal formula treatment I had great improvements with my slurred speech, this is a breakthrough for all amyotrophic lateral sclerosis sufferers, visit Health Herbal Clinic official website www. healthherbalclinic. net or email info@ healthherbalclinic. net.