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The Journal of Neuroscience, February 27, 2008, 28(9):2147-2157; doi:10.1523/JNEUROSCI.3159-07.2008

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Neurobiology of Disease
Quantitative and Functional Analyses of Spastin in the Nervous System: Implications for Hereditary Spastic Paraplegia

Joanna M. Solowska,¹ Gerardo Morfini,² Aditi Falnikar,¹ B. Timothy Himes,^1,3 Scott T. Brady,² Dongyang Huang,² and Peter W. Baas¹

¹Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, ²Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612, and ³Department of Veterans Affairs Medical Center, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to either of the following: Peter W. Baas, Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129 Email: pbaas{at}drexelmed.edu; or Gerardo Morfini, Department of Anatomy and Cell Biology, University Of Illinois at Chicago, MC512, 808 South Wood Street, Room 578, Chicago, IL 60612, Email: gmorfini{at}uic.edu

Spastin and P60-katanin are two distinct microtubule-severing proteins. Autosomal dominant mutations in the SPG4 locus corresponding to spastin are the most common cause of hereditary spastic paraplegia (HSP), a neurodegenerative disease that afflicts the adult corticospinal tracts. Here we sought to evaluate whether SPG4-based HSP is best understood as a "loss-of-function" disease. Using various rat tissues, we found that P60-katanin levels are much higher than spastin levels during development. In the adult, P60-katanin levels plunge dramatically but spastin levels decline only slightly. Quantitative data of spastin expression in specific regions of the nervous system failed to reveal any obvious explanation for the selective sensitivity of adult corticospinal tracts to loss of spastin activity. An alternative explanation relates to the fact that the mammalian spastin gene has two start codons, resulting in a 616 amino acid protein called M1 and a slightly shorter protein called M85. We found that M1 is almost absent from developing neurons and most adult neurons but comprises 20–25% of the spastin in the adult spinal cord, the location of the axons that degenerate during HSP. Experimental expression in cultured neurons of a short dysfunctional M1 polypeptide (but not a short dysfunctional M85 peptide) is deleterious to normal axonal growth. In squid axoplasm, the M1 peptide dramatically inhibits fast axonal transport, whereas the M85 peptide does not. These results are consistent with a "gain-of-function" mechanism underlying HSP wherein spastin mutations produce a cytotoxic protein in the case of M1 but not M85.

Key words: microtubule; neuron; axon; spastin; katanin; hereditary spastic paraplegia

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Received July 11, 2007; revised Dec. 19, 2007; accepted Jan. 8, 2008.

Correspondence should be addressed to either of the following: Peter W. Baas, Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129 Email: pbaas{at}drexelmed.edu; or Gerardo Morfini, Department of Anatomy and Cell Biology, University Of Illinois at Chicago, MC512, 808 South Wood Street, Room 578, Chicago, IL 60612, Email: gmorfini{at}uic.edu

This article has been cited by other articles:

				G. A. Morfini, M. Burns, L. I. Binder, N. M. Kanaan, N. LaPointe, D. A. Bosco, R. H. Brown Jr, H. Brown, A. Tiwari, L. Hayward, et al. Axonal Transport Defects in Neurodegenerative Diseases J. Neurosci., October 14, 2009; 29(41): 12776 - 12786. [Abstract] [Full Text] [PDF]

				Y. Matsushita-Ishiodori, K. Yamanaka, H. Hashimoto, M. Esaki, and T. Ogura Conserved aromatic and basic amino acid residues in the pore region of Caenorhabditis elegans spastin play critical roles in microtubule severing Genes Cells, August 1, 2009; 14(8): 925 - 940. [Abstract] [Full Text] [PDF]

				H. Sudo and Y. Maru LAPSER1/LZTS2: a pluripotent tumor suppressor linked to the inhibition of katanin-mediated microtubule severing Hum. Mol. Genet., August 15, 2008; 17(16): 2524 - 2540. [Abstract] [Full Text] [PDF]

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