Tiny worm sheds light on giant mystery about neurons

April 30, 2013, Genetics Society of America

Scientists have identified a gene that keeps our nerve fibers from clogging up. Researchers in Ken Miller's laboratory at the Oklahoma Medical Research Foundation (OMRF) found that the unc-16 gene of the roundworm Caenorhabditis elegans encodes a gatekeeper that restricts flow of cellular organelles from the cell body to the axon, a long, narrow extension that neurons use for signaling. Organelles clogging the axon could interfere with neuronal signaling or cause the axon to degenerate, leading to neurodegenerative disorders. This research, published in the May 2013 Genetics Society of America's journal Genetics, adds an unexpected twist to our understanding of trafficking within neurons.

Proteins equivalent to UNC-16 are present in the neurons of all animals, including humans And are known to interact with proteins associated with neurodegenerative disorders in humans (Hereditary Spastic Paraplegia) and mice (Legs at Odd Angles). However, the underlying cause of these disorders is not well understood.

"Our UNC-16 study provides the first insights into a previously unrecognized trafficking system that protects axons from invasion by organelles from the cell soma," Dr. Miller said. "A breakdown in this gatekeeper may be the underlying cause of this group of disorders," he added.

This video contains four clips, each showing a different wild type (normal, non-mutant) cell body with its axon initial segment (Green). The "commissure" is the first part of the axon. Lysosome organelles (Red) can be seen moving within the axon, but they tend to return to the cell body, rather than moving deeper into the axon. Images were collected at 2 second. Playback is sped up 20-fold relative to real time. Credit: Dr. Kenneth Miller Lab, Oklahoma Medical Research Foundation

The use of the C. elegans, a tiny, translucent roundworm with only 300 neurons, enabled the discovery because the researchers were able to apply complex and imaging methods in , which would be impossible in larger animals. Dr. Miller's team tagged organelles with fluorescent proteins and then used time-lapse imaging to follow the movements of the organelles. In normal axons, organelles exited the cell body and entered the initial segment of the axon, but did not move beyond that. In axons of unc-16 , the organelles hitched a ride on tiny motors that carried them deep into the axon, where they accumulated.

This video contains five clips, each showing a different unc-16 mutant cell body (Green) with its axon initial segment (labeled "commissure". Lysosome organelles (Red) can be seen moving within the axon, but they tend to escape the axon initial segment and move deeper into the axon (unlike wild type). Images were collected at 2 second. Playback is sped up 20-fold relative to real time. Credit: Dr. Kenneth Miller Lab, Oklahoma Medical Research Foundation

Dr. Miller acknowledges there are still a lot of unanswered questions. His lab is currently investigating how UNC-16 performs its crucial gatekeeper function by looking for other mutant worms with similar phenotypes. A Commentary on the article, also published in this issue of GENETICS, calls the work "provocative", and highlights several important questions prompted by this pioneering study.

"This research once again shows how studies of simple model organisms can bring insight into complex neurodegenerative diseases in humans," said Mark Johnston, Editor-in-Chief of the journal Genetics. "This kind of basic research is necessary if we are to understand diseases that can't easily be studied in more complex animals."

Explore further: Nerve pathway for combating axon injury and stress may hold benefits for individuals with neurodegenerative disorders

More information: Edwards, Stacey L., Szi-chieh Yu, Christopher M. Hoover, Barret C. Phillips, Janet E. Richmond, and Kenneth G. Miller. An Organelle Gatekeeper Function for Caenorhabditis elegans UNC-16 (JIP3) at the Axon Initial Segment Genetics, May 2013, 194:143-161.

Commentary: Zheng, Qun and Michael L. Nonet. Title: UNC-16/JIP3/Sunday Driver: A New Cop on the Organelle Highway Genetics, May 2013, 194:35-37.

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