Neurodegenerative disease research has long been focused on understanding the underlying genes and molecules involved in the breakdown of mental function. But it is a multi-faceted process, involving some of the most complicated cell types in the human body. The main focal point has been on determining how the diseases progress and what can be done to arrest or halt that progression. The ability to stop their onset and find preventative measures is still in its infancy for many disorders.

Worms and You

However, researchers at the University of Queensland have made a small discovery that, by itself, would seem isolated to the C. elegans model organism they used in their experiment. But it may actually point a lens at a new genetic system that will lead to true methods in treating such neurodegenerative disorders.

Their study aimed at a particular gene known as lin14, a heterochronic piece of genetic material that is expressed differently depending on the stage of life the organism is at. Before explaining the function of this gene, let’s talk about the aforementioned disorders for a moment. While much research is still being done to figure out components of how they progress, one thing does seem to have made itself clear over time.

A prime starting point that belies the onset of diseases like Alzheimer’s, Parkinson’s, and other motor neuron conditions is when axonal degeneration begins. It has been observed in all these conditions and more that one of the first symptoms is the withering away or breaking of axonal connections. This, of course, also ultimately leads to the death of the attached neuron and it is quite possibly the spread of this that leads to wider brain damage.

Controlled Activation

With that noted, let’s get back to lin14. The gene’s expression exists on a gradient that changes depending on the current point in the nematode’s life cycle. It features heavy activation during the young larval stage and slopes downward significantly afterward, due to suppression from a microRNA called lin4. The actual activity of lin14 is pretty varied. It is involved in the construction of lateral body cells and in downregulation of the insulin pathway. The important part for this article though is that it is also fairly active in neurons, such as deciding the fate of certain neuron types and in guiding axon growth.

The researchers induced changes in select C. elegans that deleted the functionality of the lin14 gene. What they found is that the nematodes spontaneously started developing axonal degeneration later in life and this progressed faster and faster as time went on. The neurons that were seemingly directly targeted for such degeneration were those associated with motor functions.

Other axon defects were observed than just them breaking. Alternative possibilities included thinning of the axonal strand, random branching of the axon not toward other neurons, and the complete loss of the synaptic branch at the end of the axon responsible for sending signals and neurotransmitters to other neurons. All in all, this showcased that lin14 must have some sort of strong involvement in preventing all the various axonal degeneration symptoms from occurring.

A Lengthy Nerve

The main neuron affected in this manner is the PLM neuron, which is the primary mechanosensory neuron in the C. elegans body that extends through a major portion of its length. Directly after the embryo period, the PLM neuron has formed with its length reaching to the mid-body of the nematode. To compare the interaction between this neuron and lin14, several other organisms that also possess both were investigated.

In a similar fashion to expectations, the PLM neuron grew normally during early stages of development, but once adulthood had been reached, it became highly defective in the previously noted ways. When time lapse photography was used to observe the neuron between the stages of growth, it was clearly seen how breaks in the axon structure began to form. This also allowed them to see how lin14 and the lack of it takes effect.

Since lin14 is involved in axon guidance and, for the PLM neuron, embedding the axon end properly within the hypodermis tissue of the mid-body, this never occurs if the gene is inactivated. And, without that tissue stability holding together the axon, it begins to break down later in the nematode life cycle.

Synergistic Protection

A final thing the scientists found in their experiments is the synergistic relationship between lin14 and another genetic component known as DLK-1. The pathway the latter is involved in has been seen in mice and flies to promote axonal degeneration after injury has occurred to the neuron. When the researchers tried making C. elegans mutants with both lin14 and DLK-1 turned off, they found that PLM degeneration was greatly enhanced and sped up, with the axon breaking down far sooner than it had previously.

This was an interesting result, since axonal degeneration by itself doesn’t just spontaneously occur in mutants with only DLK-1 inactivated. When they tried a different tactic and mutated some specimens to have rpm-1, an enzyme responsible for breaking down DLK-1, not be active and have lin14 be off, they resulted in mutants with no axonal degeneration at all. Apparently a high concentration of DLK-1 was able to prevent the PLM axon from developing the negative symptoms, even in the absence of lin14.

Thus, a direct relationship protecting neurons from degeneration was found between lin14 and DLK-1.

On To Neurodegenerative Research

While it should be noted that lin14 is not a gene found in humans, the discovery of it in C. elegans implies that there are likely equivalent genes to be found in humans that work in a similar manner. Finding them may prove the key to preventing the onset of many neurodegenerative disorders, especially if they manage to work in such a simple protective manner as with nematodes. As that would indicate that upregulation of the involved genes may be enough to prevent the beginnings of axonal degeneration.

Thus, scientists must take this new information and work on finding those gene equivalents in humans. The disparate diseases may have different and individualized genes associated with them, making the task of discovery harder in the long run. But so long as they now know what sort of pathways and effects to look for, it should only be a matter of time.

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Photo CCs: Neuron-SEM-2 from Wikimedia Commons