Microtubule-severing in the axon : Implications for development , disease , and regeneration after injury

Typical neurons extend a single elongated axon that can potentially grow over great distances within the nervous system.Axons from different neurons bundle together to form nerves. Within the axon are dense arrays of microtubules that provide structural support and also act as railways for organelle transport. Individual microtubules within the array assume a variety of lengths, from just a few micrometres to over a hundred micrometres. The distribution of microtubule lengths is strongly influenced by the presence of microtubulesevering proteins that are capable of cutting long microtubules into shorter pieces. The severing proteins, termed katanin and spastin, are enzymes that break the lattice of the microtubule using energy derived from ATP hydrolysis. The levels of the severing proteins are generally higher during development than in the adult, which is consistent with the fact that microtubules are generally longer in adult axons compared to developing axons. Short microtubules are highly mobile whereas longer microtubules are stationary. Greater mobility within the microtubule array correlates with more robust axonal growth. Here, we discuss the role of microtubule-severing proteins in the development of the axon. We then propose that abnormalities in microtubule-severing may be central to axonal degeneration in a variety of neurological diseases. Finally, we posit that clinical manipulation of the severing proteins may be useful in augmenting regeneration of damaged nerves.

[1]  J. Solowska,et al.  Axonal Growth Is Sensitive to the Levels of Katanin, a Protein That Severs Microtubules , 2004, The Journal of Neuroscience.

[2]  I. Fischer,et al.  Acute Inactivation of Tau Has No Effect on Dynamics of Microtubules in Growing Axons of Cultured Sympathetic Neurons , 1998, The Journal of Neuroscience.

[3]  Bertrand Fontaine,et al.  Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia , 1999, Nature Genetics.

[4]  G. Gundersen,et al.  Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing , 2005, The Journal of cell biology.

[5]  Lei Wang,et al.  Rapid Movement of Microtubules in Axons , 2002, Current Biology.

[6]  H. Ishikawa,et al.  THE CYTOSKELETON IN MYELINATED AXONS: SERIAL SECTION STUDY , 1981 .

[7]  P. Baas,et al.  Axonal Transport of Microtubules: the Long and Short of It , 2006, Traffic.

[8]  R. Vale,et al.  Identification of katanin, an ATPase that severs and disassembles stable microtubules , 1993, Cell.

[9]  P. Baas,et al.  Microtubule Reconfiguration during Axonal Retraction Induced by Nitric Oxide , 2002, The Journal of Neuroscience.

[10]  E. Rugarli,et al.  Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. , 2002, Human molecular genetics.

[11]  M. Kirschner,et al.  Microtubule bending and breaking in living fibroblast cells. , 1999, Journal of cell science.

[12]  L. Qiang,et al.  Microtubules cut and run. , 2005, Trends in cell biology.

[13]  E. Mandelkow,et al.  Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses , 2003, Neurobiology of Aging.

[14]  F. McNally,et al.  Katanin-mediated microtubule severing can be regulated by multiple mechanisms. , 2002, Cell motility and the cytoskeleton.

[15]  L. Qiang,et al.  Tau Protects Microtubules in the Axon from Severing by Katanin , 2006, The Journal of Neuroscience.

[16]  K. Broadie,et al.  The Hereditary Spastic Paraplegia Gene, spastin, Regulates Microtubule Stability to Modulate Synaptic Structure and Function , 2004, Current Biology.

[17]  R. Vale,et al.  Katanin, the microtubule-severing ATPase, is concentrated at centrosomes. , 1996, Journal of cell science.

[18]  Bin Zhang,et al.  Axonal transport defects: a common theme in neurodegenerative diseases , 2005, Acta Neuropathologica.

[19]  P. Baas,et al.  An Essential Role for Katanin in Severing Microtubules in the Neuron , 1999, The Journal of cell biology.

[20]  F. McNally,et al.  Katanin is responsible for the M-phase microtubule-severing activity in Xenopus eggs. , 1998, Molecular biology of the cell.

[21]  Marileen Dogterom,et al.  A bending mode analysis for growing microtubules: evidence for a velocity-dependent rigidity. , 2004, Biophysical journal.

[22]  R. Vale,et al.  Microtubule disassembly by ATP-dependent oligomerization of the AAA enzyme katanin. , 1999, Science.

[23]  S. Heidemann,et al.  Polarity orientation of axonal microtubules , 1981, The Journal of cell biology.

[24]  D. Bray,et al.  Serial analysis of microtubules in cultured rat sensory axons , 1981, Journal of neurocytology.

[25]  H. Joshi,et al.  Inhibition of microtubule nucleation at the neuronal centrosome compromises axon growth , 1994, Neuron.

[26]  P. Baas,et al.  Microtubules released from the neuronal centrosome are transported into the axon. , 1995, Journal of cell science.

[27]  P. Bondallaz,et al.  Role of the microtubule destabilizing proteins SCG10 and stathmin in neuronal growth. , 2004, Journal of neurobiology.

[28]  S. Sharma,et al.  Axonal transport and transcellular transfer of nucleosides and polyamines in intact and regenerating optic nerves of goldfish: speculation on the axonal regulation of periaxonal cell metabolism , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[29]  L. Qiang,et al.  Neuronal microtubules: when the MAP is the roadblock. , 2005, Trends in cell biology.

[30]  D. Cleveland,et al.  Going new places using an old MAP: tau, microtubules and human neurodegenerative disease. , 2001, Current opinion in cell biology.

[31]  K. Zinn,et al.  Drosophila Spastin Regulates Synaptic Microtubule Networks and Is Required for Normal Motor Function , 2004, PLoS biology.

[32]  K. Kalil,et al.  Reorganization and Movement of Microtubules in Axonal Growth Cones and Developing Interstitial Branches , 1999, The Journal of Neuroscience.