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.
The use of the model organism C. elegans, a tiny, translucent roundworm with only 300 neurons, enabled the discovery because the researchers were able to apply complex genetic techniques and imaging methods in living organisms, 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 mutants, the organelles hitched a ride on tiny motors that carried them deep into the axon, where they accumulated.
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.”
Genetics, May 2013, 194:143-161.
FUNDING: This work was supported by grants from the NIH (GM080765 to K.G.M; R01 MH073156 to J.E.R.) and a grant from the Oklahoma Center for the Advancement of Science to K.G.M. (HR06-078).COMMENTARY CITATION: Zheng, Qun and Michael L. Nonet.
ABOUT GSA: Founded in 1931, the Genetics Society of America (GSA) is the professional membership organization for scientific researchers, educators, bioengineers, bioinformaticians and others interested in the field of genetics. Its nearly 5,000 members work to advance knowledge in the basic mechanisms of inheritance, from the molecular to the population level. The GSA is dedicated to promoting research in genetics and to facilitating communication among geneticists worldwide through its conferences, including the biennial conference on Model Organisms to Human Biology, an interdisciplinary meeting on current and cutting edge topics in genetics research, as well as annual and biennial meetings that focus on the genetics of particular organisms, including C. elegans, Drosophila, fungi, mice, yeast, and zebrafish. GSA publishes GENETICS, a leading journal in the field and an online, open-access journal, G3: Genes|Genomes|Genetics. For more information about GSA, please visit www.genetics-gsa.org. Also follow GSA on Facebook at facebook.com/GeneticsGSA and on Twitter @GeneticsGSA.
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