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Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing

Mutations in the AAA adenosine triphosphatase (ATPase) Spastin (SPG4) cause an autosomal dominant form of hereditary spastic paraplegia, which is a retrograde axonopathy primarily characterized pathologically by the degeneration of long spinal neurons in the corticospinal tracts and the dorsal colum...

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Autores principales: Evans, Katia J., Gomes, Edgar R., Reisenweber, Steven M., Gundersen, Gregg G., Lauring, Brett P.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171748/
https://www.ncbi.nlm.nih.gov/pubmed/15716377
http://dx.doi.org/10.1083/jcb.200409058
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author Evans, Katia J.
Gomes, Edgar R.
Reisenweber, Steven M.
Gundersen, Gregg G.
Lauring, Brett P.
author_facet Evans, Katia J.
Gomes, Edgar R.
Reisenweber, Steven M.
Gundersen, Gregg G.
Lauring, Brett P.
author_sort Evans, Katia J.
collection PubMed
description Mutations in the AAA adenosine triphosphatase (ATPase) Spastin (SPG4) cause an autosomal dominant form of hereditary spastic paraplegia, which is a retrograde axonopathy primarily characterized pathologically by the degeneration of long spinal neurons in the corticospinal tracts and the dorsal columns. Using recombinant Spastin, we find that six mutant forms of Spastin, including three disease-associated forms, are severely impaired in ATPase activity. In contrast to a mutation designed to prevent adenosine triphosphate (ATP) binding, an ATP hydrolysis–deficient Spastin mutant predicted to remain kinetically trapped on target proteins decorates microtubules in transfected cells. Analysis of disease-associated missense mutations shows that some more closely resemble the canonical hydrolysis mutant, whereas others resemble the ATP-binding mutant. Using real-time imaging, we show that Spastin severs microtubules when added to permeabilized, cytosol-depleted cells stably expressing GFP-tubulin. Using purified components, we also show that Spastin interacts directly with microtubules and is sufficient for severing. These studies suggest that defects in microtubule severing are a cause of axonal degeneration in human disease.
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spelling pubmed-21717482008-03-05 Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing Evans, Katia J. Gomes, Edgar R. Reisenweber, Steven M. Gundersen, Gregg G. Lauring, Brett P. J Cell Biol Research Articles Mutations in the AAA adenosine triphosphatase (ATPase) Spastin (SPG4) cause an autosomal dominant form of hereditary spastic paraplegia, which is a retrograde axonopathy primarily characterized pathologically by the degeneration of long spinal neurons in the corticospinal tracts and the dorsal columns. Using recombinant Spastin, we find that six mutant forms of Spastin, including three disease-associated forms, are severely impaired in ATPase activity. In contrast to a mutation designed to prevent adenosine triphosphate (ATP) binding, an ATP hydrolysis–deficient Spastin mutant predicted to remain kinetically trapped on target proteins decorates microtubules in transfected cells. Analysis of disease-associated missense mutations shows that some more closely resemble the canonical hydrolysis mutant, whereas others resemble the ATP-binding mutant. Using real-time imaging, we show that Spastin severs microtubules when added to permeabilized, cytosol-depleted cells stably expressing GFP-tubulin. Using purified components, we also show that Spastin interacts directly with microtubules and is sufficient for severing. These studies suggest that defects in microtubule severing are a cause of axonal degeneration in human disease. The Rockefeller University Press 2005-02-14 /pmc/articles/PMC2171748/ /pubmed/15716377 http://dx.doi.org/10.1083/jcb.200409058 Text en Copyright © 2005, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Evans, Katia J.
Gomes, Edgar R.
Reisenweber, Steven M.
Gundersen, Gregg G.
Lauring, Brett P.
Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing
title Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing
title_full Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing
title_fullStr Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing
title_full_unstemmed Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing
title_short Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing
title_sort linking axonal degeneration to microtubule remodeling by spastin-mediated microtubule severing
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171748/
https://www.ncbi.nlm.nih.gov/pubmed/15716377
http://dx.doi.org/10.1083/jcb.200409058
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