Genetic Analysis of a Novel Tubulin Mutation That Redirects Synaptic Vesicle Targeting and Causes Neurite Degeneration in C. elegans

Jiun-Min Hsu, Chun-Hao Chen, Yen-Chih Chen, Kent L McDonald, Mark Gurling, Albert Lee, Gian Garriga and Chun-Liang Pan

PLOS Genetics, 2014, vol. 10, issue 11, 1-16

Abstract: Neuronal cargos are differentially targeted to either axons or dendrites, and this polarized cargo targeting critically depends on the interaction between microtubules and molecular motors. From a forward mutagenesis screen, we identified a gain-of-function mutation in the C. elegans α-tubulin gene mec-12 that triggered synaptic vesicle mistargeting, neurite swelling and neurodegeneration in the touch receptor neurons. This missense mutation replaced an absolutely conserved glycine in the H12 helix with glutamic acid, resulting in increased negative charges at the C-terminus of α-tubulin. Synaptic vesicle mistargeting in the mutant neurons was suppressed by reducing dynein function, suggesting that aberrantly high dynein activity mistargeted synaptic vesicles. We demonstrated that dynein showed preference towards binding mutant microtubules over wild-type in microtubule sedimentation assay. By contrast, neurite swelling and neurodegeneration were independent of dynein and could be ameliorated by genetic paralysis of the animal. This suggests that mutant microtubules render the neurons susceptible to recurrent mechanical stress induced by muscle activity, which is consistent with the observation that microtubule network was disorganized under electron microscopy. Our work provides insights into how microtubule-dynein interaction instructs synaptic vesicle targeting and the importance of microtubule in the maintenance of neuronal structures against constant mechanical stress.Author Summary: Axons and dendrites are two classes of neuronal process that differ in their functions and molecular compositions. Proteins important for synaptic functions are mostly synthesized in the cell body and sorted differentially into the axon or dendrites. Microtubules in the axon and dendrite maintain their structural integrity and regulate polarized protein transport into these compartments. We identified a novel α-tubulin mutation in C. elegans that caused mistargeting of synaptic vesicles and induced progressive neurite swelling, which resulted in late-onset neurodegeneration. We showed that this tubulin mutation weakened microtubule network and abnormally increased microtubule affinity for dynein, a motor protein responsible for cargo sorting to the dendrite. This enhanced microtubule-dynein affinity is due to augmented negative charge at the carboxyl terminus of α-tubulin. Neurite swelling and neurodegeneration could be ameliorated by reduced physical activity, suggesting that recurrent mechanical strain from muscle contraction jeopardized neurite integrity in the long run. Mutations in α- and β-tubulins are found in human neurological diseases; our findings therefore contribute to understanding the pathogenic mechanism of human neurological diseases associated with tubulin mutations.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1004715

DOI: 10.1371/journal.pgen.1004715

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