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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of cell biology 2005-02, Vol.168 (4), p.599-606
Main Authors: Evans, Katia J, Gomes, Edgar R, Reisenweber, Steven M, Gundersen, Gregg G, Lauring, Brett P
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Adenosine triphosphatases
Adenosine Triphosphatases - genetics
Adenosine Triphosphatases - metabolism
Animals
Antibodies
Axons - metabolism
Cellular biology
COS cells
Enzymes
Gels
Genetic mutation
HeLa Cells
Humans
Hydrolysis
Mice
Microtubules
Microtubules - metabolism
Muscle spasticity
Mutation
Mutation - genetics
Neurological disorders
Neurons
NIH 3T3 Cells
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Spastic Paraplegia, Hereditary - genetics
Spastic Paraplegia, Hereditary - metabolism
Spastin
Tubulin - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200409058