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

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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.

Vyšlo v časopise: Genetic Analysis of a Novel Tubulin Mutation That Redirects Synaptic Vesicle Targeting and Causes Neurite Degeneration in. PLoS Genet 10(11): e32767. doi:10.1371/journal.pgen.1004715
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004715

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