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.
Skip Nav Destination
Article navigation
14 February 2005
Article|
February 14 2005
Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing
Katia J. Evans,
Katia J. Evans
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
2Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Search for other works by this author on:
Edgar R. Gomes,
Edgar R. Gomes
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
3Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Search for other works by this author on:
Steven M. Reisenweber,
Steven M. Reisenweber
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
2Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Search for other works by this author on:
Gregg G. Gundersen,
Gregg G. Gundersen
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
3Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Search for other works by this author on:
Brett P. Lauring
Brett P. Lauring
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
2Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Search for other works by this author on:
Katia J. Evans
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
2Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Edgar R. Gomes
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
3Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Steven M. Reisenweber
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
2Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Gregg G. Gundersen
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
3Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Brett P. Lauring
1Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
2Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032
Correspondence to Brett P. Lauring: [email protected]
Received:
September 10 2004
Accepted:
December 22 2004
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 168 (4): 599–606.
Article history
Received:
September 10 2004
Accepted:
December 22 2004
Citation
Katia J. Evans, Edgar R. Gomes, Steven M. Reisenweber, Gregg G. Gundersen, Brett P. Lauring; Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing . J Cell Biol 14 February 2005; 168 (4): 599–606. doi: https://doi.org/10.1083/jcb.200409058
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Sign in via your Institution
Sign in via your InstitutionSuggested Content
Email alerts
Advertisement
Advertisement