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• W2038204861 endingPage "1867" @default.
• W2038204861 startingPage "1856" @default.
• W2038204861 abstract "Mutations to the SPG4 gene encoding the microtubule-severing protein spastin are the most common cause of hereditary spastic paraplegia. Haploinsufficiency, the prevalent model for the disease, cannot readily explain many of its key aspects, such as its adult onset or its specificity for the corticospinal tracts. Treatment strategies based solely on haploinsufficiency are therefore likely to fail. Toward developing effective therapies, here we investigated potential gain-of-function effects of mutant spastins. The full-length human spastin isoform called M1 or a slightly shorter isoform called M87, both carrying the same pathogenic mutation C448Y, were expressed in three model systems: primary rat cortical neurons, fibroblasts, and transgenic Drosophila . Although both isoforms had ill effects on motor function in transgenic flies and decreased neurite outgrowth from primary cortical neurons, mutant M1 was notably more toxic than mutant M87. The observed phenotypes did not result from dominant-negative effects of mutated spastins. Studies in cultured cells revealed that microtubules can be heavily decorated by mutant M1 but not mutant M87. Microtubule-bound mutant M1 decreased microtubule dynamics, whereas unbound M1 or M87 mutant spastins increased microtubule dynamics. The alterations in microtubule dynamics observed in the presence of mutated spastins are not consistent with haploinsufficiency and are better explained by a gain-of-function mechanism. Our results fortify a model wherein toxicity of mutant spastin proteins, especially mutant M1, contributes to axonal degeneration in the corticospinal tracts. Furthermore, our results provide details on the mechanism of the toxicity that may chart a course toward more effective treatment regimens." @default.
• W2038204861 created "2016-06-24" @default.
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• W2038204861 date "2014-01-29" @default.
• W2038204861 modified "2023-10-06" @default.
• W2038204861 title "Pathogenic Mutation of Spastin Has Gain-of-Function Effects on Microtubule Dynamics" @default.
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• W2038204861 doi "https://doi.org/10.1523/jneurosci.3309-13.2014" @default.
• W2038204861 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3905148" @default.
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