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Functional differences of short and long isoforms of spastin harboring missense mutation
Mutations of the SPG4 (SPAST) gene encoding for spastin protein are the main causes of hereditary spastic paraplegia. Spastin binds to microtubules and severs them through the enzymatic activity of its AAA domain. Several missense mutations located in this domain lead to stable, nonsevering spastins...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177001/ https://www.ncbi.nlm.nih.gov/pubmed/30213879 http://dx.doi.org/10.1242/dmm.033704 |
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author | Plaud, Clément Joshi, Vandana Kajevu, Natallie Poüs, Christian Curmi, Patrick A. Burgo, Andrea |
author_facet | Plaud, Clément Joshi, Vandana Kajevu, Natallie Poüs, Christian Curmi, Patrick A. Burgo, Andrea |
author_sort | Plaud, Clément |
collection | PubMed |
description | Mutations of the SPG4 (SPAST) gene encoding for spastin protein are the main causes of hereditary spastic paraplegia. Spastin binds to microtubules and severs them through the enzymatic activity of its AAA domain. Several missense mutations located in this domain lead to stable, nonsevering spastins that decorate a subset of microtubules, suggesting a possible negative gain-of-function mechanism for these mutants. Of the two main isoforms of spastin, only mutations of the long isoform, M1, are supposed to be involved in the onset of the pathology, leaving the role of the ubiquitously expressed shorter one, M87, not fully investigated and understood. Here, we show that two isoforms of spastin harboring the same missense mutation bind and bundle different subsets of microtubules in HeLa cells, and likely stabilize them by increasing the level of acetylated tubulin. However, only mutated M1 has the ability to interact with wild-type M1, and decorates a subset of perinuclear microtubules associated with the endoplasmic reticulum that display higher resistance to microtubule depolymerization and increased intracellular ionic strength, compared with those decorated by mutated M87. We further show that only mutated M1 decorates microtubules of proximal axons and dendrites, and strongly impairs axonal transport in cortical neurons through a mechanism likely independent of the microtubule-severing activity of this protein. |
format | Online Article Text |
id | pubmed-6177001 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-61770012018-10-16 Functional differences of short and long isoforms of spastin harboring missense mutation Plaud, Clément Joshi, Vandana Kajevu, Natallie Poüs, Christian Curmi, Patrick A. Burgo, Andrea Dis Model Mech Research Article Mutations of the SPG4 (SPAST) gene encoding for spastin protein are the main causes of hereditary spastic paraplegia. Spastin binds to microtubules and severs them through the enzymatic activity of its AAA domain. Several missense mutations located in this domain lead to stable, nonsevering spastins that decorate a subset of microtubules, suggesting a possible negative gain-of-function mechanism for these mutants. Of the two main isoforms of spastin, only mutations of the long isoform, M1, are supposed to be involved in the onset of the pathology, leaving the role of the ubiquitously expressed shorter one, M87, not fully investigated and understood. Here, we show that two isoforms of spastin harboring the same missense mutation bind and bundle different subsets of microtubules in HeLa cells, and likely stabilize them by increasing the level of acetylated tubulin. However, only mutated M1 has the ability to interact with wild-type M1, and decorates a subset of perinuclear microtubules associated with the endoplasmic reticulum that display higher resistance to microtubule depolymerization and increased intracellular ionic strength, compared with those decorated by mutated M87. We further show that only mutated M1 decorates microtubules of proximal axons and dendrites, and strongly impairs axonal transport in cortical neurons through a mechanism likely independent of the microtubule-severing activity of this protein. The Company of Biologists Ltd 2018-09-01 2018-09-10 /pmc/articles/PMC6177001/ /pubmed/30213879 http://dx.doi.org/10.1242/dmm.033704 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Plaud, Clément Joshi, Vandana Kajevu, Natallie Poüs, Christian Curmi, Patrick A. Burgo, Andrea Functional differences of short and long isoforms of spastin harboring missense mutation |
title | Functional differences of short and long isoforms of spastin harboring missense mutation |
title_full | Functional differences of short and long isoforms of spastin harboring missense mutation |
title_fullStr | Functional differences of short and long isoforms of spastin harboring missense mutation |
title_full_unstemmed | Functional differences of short and long isoforms of spastin harboring missense mutation |
title_short | Functional differences of short and long isoforms of spastin harboring missense mutation |
title_sort | functional differences of short and long isoforms of spastin harboring missense mutation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177001/ https://www.ncbi.nlm.nih.gov/pubmed/30213879 http://dx.doi.org/10.1242/dmm.033704 |
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