Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hereditary spastic paraplegias: membrane traffic and the motor pathway

An Erratum to this article was published on 20 January 2011

This article has been updated

Key Points

  • The hereditary spastic paraplegias (HSPs) are genetic conditions in which spasticity of the legs is caused by degeneration or abnormal development of the distal ends of the corticospinal tract's longest axons.

  • Mutations in many different genes can cause HSPs. The proteins encoded by these genes seem to fall into a few functional groups, and there are multiple examples of direct interactions among proteins associated with HSPs.

  • An important group of proteins encoded by HSP genes are involved in membrane trafficking and organelle morphogenesis. This group includes three proteins — spastin, atlastin-1 and receptor expression-enhancing protein 1 (REEP1) — that are involved in membrane shaping at the tubular endoplasmic reticulum.

  • Strumpellin is also part of a complex that is involved in membrane shaping, but at endosomes — where this complex interacts with the actin cytoskeleton and is thought to be required for fission of endosomal transport tubules.

  • At least three members of the membrane traffic group of proteins associated with HSP are also implicated in bone morphogenetic protein (BMP) signalling. The best characterized of these is non imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1) and its Drosophila melanogaster homologue, spichthyin, which regulates the endosomal trafficking and degradation of BMP receptors.

  • Study of the HSPs is providing insights into the basic cellular pathways that are required for axonal maintenance and that are involved in axonal degeneration. This provides the foundation for future work aimed at producing rationally designed therapies that are built on a thorough knowledge of the molecular and cellular pathology of distal axonal degeneration in HSPs.

Abstract

Voluntary movement is a fundamental way in which animals respond to, and interact with, their environment. In mammals, the main CNS pathway controlling voluntary movement is the corticospinal tract, which encompasses connections between the cerebral motor cortex and the spinal cord. Hereditary spastic paraplegias (HSPs) are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness. Recent work aimed at elucidating the molecular cell biology underlying the HSPs has revealed the importance of basic cellular processes — especially membrane trafficking and organelle morphogenesis and distribution — in axonal maintenance and degeneration.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Spastin domain structure and interacting proteins.
Figure 2: The spastin–Atlastin–REEP–Reticulon complex at the ER.
Figure 3: The strumpellin–WASH complex.
Figure 4: Model of NIPA1 action on bone morphogenetic protein receptor type-2 (BMPRII) traffic.

Change history

  • 17 December 2010

    On page 37 of the above article, in Figure 3a, the protein structure labelled VPS35C was incorrectly labelled VPS39C. This has been corrected in the online version.

References

  1. Goldstein, A. Y., Wang, X. & Schwarz, T. L. Axonal transport and the delivery of pre-synaptic components. Curr. Opin. Neurobiol. 18, 495–503 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Harding, A. E. The Hereditary Ataxias and Related Disorders (Churchill Livingston, Edinburgh, 1984).

    Google Scholar 

  3. DeLuca, G. C., Ebers, G. C. & Esiri, M. M. Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain 127, 1009–1018 (2004).

    CAS  PubMed  Article  Google Scholar 

  4. Fischer, L. R. et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185, 232–240 (2004).

    PubMed  Article  Google Scholar 

  5. Harding, A. E. Hereditary spastic paraplegias. Semin. Neurol. 13, 333–336 (1993).

    CAS  PubMed  Article  Google Scholar 

  6. Fink, J. K. Hereditary spastic paraplegia. Curr. Neurol. Neurosci. Rep. 6, 65–76 (2006).

    CAS  PubMed  Article  Google Scholar 

  7. McDermott, C. J. & Shaw, P. J. Hereditary spastic paraplegia. Int. Rev. Neurobiol. 53, 191–204 (2002).

    CAS  PubMed  Article  Google Scholar 

  8. Reid, E. The hereditary spastic paraplegias. J. Neurol. 246, 995–1003 (1999).

    CAS  PubMed  Article  Google Scholar 

  9. Salinas, S., Proukakis, C., Crosby, A. & Warner, T. T. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol. 7, 1127–1138 (2008).

    CAS  PubMed  Article  Google Scholar 

  10. Reid, E. & Rugarli, E. in The Online Metabolic and Molecular Bases of Inherited Diseases http://www.ommbid.com/OMMBID/the_online_metabolic_and_molecular_bases_of_inherited_disease/b/abstract/part28/ch228.1 (2010).

    Google Scholar 

  11. Hazan, J. et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nature Genet. 23, 296–303 (1999). This paper identified SPG4 , which encodes the spastin protein, as the gene most commonly mutated in HSP.

    CAS  PubMed  Article  Google Scholar 

  12. Claudiani, P., Riano, E., Errico, A., Andolfi, G. & Rugarli, E. I. Spastin subcellular localization is regulated through usage of different translation start sites and active export from the nucleus. Exp. Cell Res. 309, 358–369 (2005).

    CAS  PubMed  Article  Google Scholar 

  13. Mancuso, G. & Rugarli, E. I. A cryptic promoter in the first exon of the SPG4 gene directs the synthesis of the 60-kDa spastin isoform. BMC Biol. 6, 31 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. Salinas, S., Carazo-Salas, R. E., Proukakis, C., Schiavo, G. & Warner, T. T. Spastin and microtubules: Functions in health and disease. J. Neurosci. Res. 85, 2778–2782 (2007).

    CAS  Article  PubMed  Google Scholar 

  15. Roll-Mecak, A. & McNally, F. J. Microtubule-severing enzymes. Curr. Opin. Cell Biol. 22, 96–103 (2010).

    CAS  PubMed  Article  Google Scholar 

  16. White, S. R., Evans, K. J., Lary, J., Cole, J. L. & Lauring, B. Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing. J. Cell Biol. 176, 995–1005 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. White, S. R. & Lauring, B. AAA+ ATPases: achieving diversity of function with conserved machinery. Traffic 8, 1657–1667 (2007).

    CAS  PubMed  Article  Google Scholar 

  18. Roll-Mecak, A. & Vale, R. D. Structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin. Nature 451, 363–367 (2008). This paper presented the structure of the spastin AAA ATPase domain and shows how spastin assembles into a hexameric ring.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Connell, J. W., Lindon, C., Luzio, J. P. & Reid, E. Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic 10, 42–56 (2009). This paper showed that spastin is recruited to membrane sites in an isoform-specific fashion. Together with reference 30, it showed that spastin is required for the completion of cytokinesis.

    CAS  PubMed  Article  Google Scholar 

  20. Sanderson, C. M. et al. Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners. Hum. Mol. Genet. 15, 307–318 (2006). Together with reference 45, this paper presented the first evidence that two HSP proteins were binding partners.

    CAS  PubMed  Article  Google Scholar 

  21. Hu, J. et al. A class of dynamin-like GTPases involved in the generation of the tubular ER network. Cell 138, 549–561 (2009). Together with reference 40, this paper showed that Atlastin GTPases have crucial functions in defining the morphology of the ER.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Park, S. H., Zhu, P. P., Parker, R. L. & Blackstone, C. Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J. Clin. Invest. 120, 1097–1110 (2010). This paper showed that spastin, Atlastins and REEPs all act in concert to shape the ER reticular membrane.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Ciccarelli, F. D. et al. The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Genomics 81, 437–441 (2003).

    CAS  PubMed  Article  Google Scholar 

  24. Hurley, J. H. ESCRT complexes and the biogenesis of multivesicular bodies. Curr. Opin. Cell Biol. 20, 4–11 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Raiborg, C. & Stenmark, H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445–452 (2009).

    CAS  Article  PubMed  Google Scholar 

  26. Slagsvold, T., Pattni, K., Malerod, L. & Stenmark, H. Endosomal and non-endosomal functions of ESCRT proteins. Trends Cell Biol. 16, 317–326 (2006).

    CAS  Article  PubMed  Google Scholar 

  27. Hurley, J. H. & Hanson, P. I. Membrane budding and scission by the ESCRT machinery: it's all in the neck. Nature Rev. Mol. Cell Biol. 11, 556–566 (2010).

    CAS  Article  Google Scholar 

  28. Reid, E. et al. The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B. Hum. Mol. Genet. 14, 19–38 (2005).

    CAS  PubMed  Article  Google Scholar 

  29. Agromayor, M. et al. Essential role of hIST1 in cytokinesis. Mol. Biol. Cell 20, 1374–1387 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Yang, D. et al. Structural basis for midbody targeting of spastin by the ESCRT-III protein CHMP1B. Nature Struct. Mol. Biol. 15, 1278–1286 (2008).

    CAS  Article  Google Scholar 

  31. Piel, M., Nordberg, J., Euteneuer, U. & Bornens, M. Centrosome-dependent exit of cytokinesis in animal cells. Science 291, 1550–1553 (2001).

    CAS  PubMed  Article  Google Scholar 

  32. Echard, A., Hickson, G. R., Foley, E. & O'Farrell, P. H. Terminal cytokinesis events uncovered after an RNAi screen. Curr. Biol. 14, 1685–1693 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Morita, E. et al. Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J. 26, 4215–4227 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Carlton, J. G. & Martin-Serrano, J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 316, 1908–1912 (2007).

    CAS  Article  PubMed  Google Scholar 

  35. Riano, E. et al. Pleiotropic effects of spastin on neurite growth depending on expression levels. J. Neurochem. 108, 1277–1288 (2009).

    CAS  PubMed  Article  Google Scholar 

  36. Yu, W. et al. The microtubule-severing proteins spastin and katanin participate differently in the formation of axonal branches. Mol. Biol. Cell 19, 1485–1498 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Mannan, A. U. et al. ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am. J. Hum. Genet. 79, 351–357 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Shirane, M. & Nakayama, K. I. Protrudin induces neurite formation by directional membrane trafficking. Science 314, 818–821 (2006).

    CAS  PubMed  Article  Google Scholar 

  39. Rismanchi, N., Soderblom, C., Stadler, J., Zhu, P. P. & Blackstone, C. Atlastin GTPases are required for Golgi apparatus and ER morphogenesis. Hum. Mol. Genet. 17, 1591–1604 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Orso, G. et al. Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin. Nature 460, 978–983 (2009).

    CAS  PubMed  Article  Google Scholar 

  41. Zhu, P. P., Soderblom, C., Tao-Cheng, J. H., Stadler, J. & Blackstone, C. SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. Hum. Mol. Genet. 15, 1343–1353 (2006).

    CAS  PubMed  Article  Google Scholar 

  42. Ridge, R. W., Uozumi, Y., Plazinski, J., Hurley, U. A. & Williamson, R. E. Developmental transitions and dynamics of the cortical ER of Arabidopsis cells seen with green fluorescent protein. Plant Cell Physiol. 40, 1253–1261 (1999).

    CAS  PubMed  Article  Google Scholar 

  43. Shibata, Y., Hu, J., Kozlov, M. M. & Rapoport, T. A. Mechanisms shaping the membranes of cellular organelles. Annu. Rev. Cell Dev. Biol. 25, 329–354 (2009).

    CAS  PubMed  Article  Google Scholar 

  44. Voeltz, G. K., Prinz, W. A., Shibata, Y., Rist, J. M. & Rapoport, T. A. A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124, 573–586 (2006).

    CAS  Article  PubMed  Google Scholar 

  45. Evans, K. et al. Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Proc. Natl Acad. Sci. USA 103, 10666–10671 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. Mannan, A. U. et al. Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with Reticulon 1 an endoplasmic reticulum protein. Neurogenetics 7, 93–103 (2006).

    CAS  PubMed  Article  Google Scholar 

  47. Valdmanis, P. N. et al. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am. J. Hum. Genet. 80, 152–161 (2007).

    CAS  PubMed  Article  Google Scholar 

  48. Gomez, T. S. & Billadeau, D. D. A FAM21-containing WASH complex regulates retromer-dependent sorting. Dev. Cell 17, 699–711 (2009). Together with reference 49, this paper defined the role of the strumpellin–WASH complex in actin regulation and tubulation at endosomes.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Derivery, E. et al. The Arp2/3 activator WASH controls the fission of endosomes through a large multiprotein complex. Dev. Cell 17, 712–723 (2009).

    CAS  PubMed  Article  Google Scholar 

  50. Harbour, M. et al. The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. J. Cell Sci. 123, 3703–3717 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Insall, R. H. & Machesky, L. M. Actin dynamics at the leading edge: from simple machinery to complex networks. Dev. Cell 17, 310–322 (2009).

    CAS  PubMed  Article  Google Scholar 

  52. Clemen, C. S. et al. Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases. Brain 133, 2920–2941 (2010).

    PubMed  Article  Google Scholar 

  53. Wood, J. D. et al. The microtubule-severing protein Spastin is essential for axon outgrowth in the zebrafish embryo. Hum. Mol. Genet. 15, 2763–2771 (2006).

    CAS  PubMed  Article  Google Scholar 

  54. Tarrade, A. et al. A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition. Hum. Mol. Genet. 15, 3544–3558 (2006).

    CAS  PubMed  Article  Google Scholar 

  55. Kasher, P. R. et al. Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients. J. Neurochem. 110, 34–44 (2009).

    CAS  PubMed  Article  Google Scholar 

  56. Keshishian, H. & Kim, Y. S. Orchestrating development and function: retrograde BMP signaling in the Drosophila nervous system. Trends Neurosci. 27, 143–147 (2004).

    CAS  PubMed  Article  Google Scholar 

  57. O'Connor-Giles, K. M., Ho, L. L. & Ganetzky, B. Nervous wreck interacts with thickveins and the endocytic machinery to attenuate retrograde BMP signaling during synaptic growth. Neuron 58, 507–518 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Charron, F. & Tessier-Lavigne, M. The Hedgehog, TGF-beta/BMP and Wnt families of morphogens in axon guidance. Adv. Exp. Med. Biol. 621, 116–133 (2007).

    PubMed  Article  Google Scholar 

  59. Wen, Z. et al. BMP gradients steer nerve growth cones by a balancing act of LIM kinase and Slingshot phosphatase on ADF/cofilin. J. Cell Biol. 178, 107–119 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Lasorella, A. et al. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 442, 471–474 (2006).

    CAS  PubMed  Article  Google Scholar 

  61. Aberle, H. et al. wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron 33, 545–558 (2002).

    CAS  PubMed  Article  Google Scholar 

  62. Ellis, J. E., Parker, L., Cho, J. & Arora, K. Activin signaling functions upstream of Gbb to regulate synaptic growth at the Drosophila neuromuscular junction. Dev. Biol. 342, 121–133 (2010).

    CAS  PubMed  Article  Google Scholar 

  63. Wang, X., Shaw, W. R., Tsang, H. T., Reid, E. & O'Kane, C. J. Drosophila spichthyin inhibits BMP signaling and regulates synaptic growth and axonal microtubules. Nature Neurosci. 10, 177–185 (2007). Together with reference 65, this was the first paper to identify abnormal BMP signalling as a potential pathogenic mechanism in HSP.

    CAS  PubMed  Article  Google Scholar 

  64. Matsuura, I., Taniguchi, J., Hata, K., Saeki, N. & Yamashita, T. BMP inhibition enhances axonal growth and functional recovery after spinal cord injury. J. Neurochem. 105, 1471–1479 (2008).

    CAS  PubMed  Article  Google Scholar 

  65. Tsang, H. T. et al. The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling. Hum. Mol. Genet. 18, 3805–3821 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Fassier, C. et al. Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway. Nature Neurosci. 13, 1380–1387 (2010). This paper suggests that abnormal BMP signalling is a cause of axonopathy in a vertebrate model of SPG3A.

    CAS  PubMed  Article  Google Scholar 

  67. Goytain, A., Hines, R. M., El-Husseini, A. & Quamme, G. A. NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter. J. Biol. Chem. 282, 8060–8068 (2007).

    CAS  PubMed  Article  Google Scholar 

  68. Zhao, J. et al. Hereditary spastic paraplegia-associated mutations in the NIPA1 gene and its Caenorhabditis elegans homolog trigger neural degeneration in vitro and in vivo through a gain-of-function mechanism. J. Neurosci. 28, 13938–13951 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Hao, J. et al. In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS Chem. Biol. 5, 245–253 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Bakowska, J. C., Jupille, H., Fatheddin, P., Puertollano, R. & Blackstone, C. Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking. Mol. Biol. Cell 18, 1683–1692 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Eastman, S. W., Yassaee, M. & Bieniasz, P. D. A role for ubiquitin ligases and Spartin/SPG20 in lipid droplet turnover. J. Cell Biol. 184, 881–894 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Edwards, T. L. et al. Endogenous spartin (SPG20) is recruited to endosomes and lipid droplets and interacts with the ubiquitin E3 ligases AIP4 and AIP5. Biochem. J. 423, 31–39 (2009).

    CAS  PubMed  Article  Google Scholar 

  73. Hooper, C., Puttamadappa, S., Loring, Z., Shekhtman, A. & Bakowska, J. Spartin activates atrophin-1-interacting protein 4 (AIP4) E3 ubiquitin ligase and promotes ubiquitination of adipophilin on lipid droplets. BMC Biology 8, 72 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. Szymanski, K. M. et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc. Natl Acad. Sci. USA 104, 20890–20895 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. Daisuke, I. & Norihiro, S. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann. Neurol. 61, 237–250 (2007).

    Article  CAS  Google Scholar 

  76. Farese, R. V., Jr & Walther, T. C. Lipid droplets finally get a little R-E-S-P-E-C.-T. Cell 139, 855–860 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Yamanaka, K., Miller, T. M., McAlonis-Downes, M., Chun, S. J. & Cleveland, D. W. Progressive spinal axonal degeneration and slowness in ALS2-deficient mice. Ann. Neurol. 60, 95–104 (2006).

    CAS  PubMed  Article  Google Scholar 

  78. Deng, H. X. et al. Distal axonopathy in an alsin-deficient mouse model. Hum. Mol. Genet. 16, 2911–2920 (2007).

    CAS  PubMed  Article  Google Scholar 

  79. Otomo, A. et al. ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. Hum. Mol. Genet. 12, 1671–1687 (2003).

    CAS  PubMed  Article  Google Scholar 

  80. Devon, R. S. et al. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc. Natl Acad. Sci. USA 103, 9595–9600 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. Lai, C. et al. Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. J. Neurosci. 26, 11798–11806 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Reid, E. et al. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am. J. Hum. Genet. 71, 1189–1194 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Goizet, C. et al. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Hum. Mutat. 30, E376–385 (2009).

    PubMed  Article  Google Scholar 

  84. Hirokawa, N. & Noda, Y. Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol. Rev. 88, 1089–1118 (2008).

    CAS  PubMed  Article  Google Scholar 

  85. Hirokawa, N., Nitta, R. & Okada, Y. The mechanisms of kinesin motor motility: lessons from the monomeric motor KIF1A. Nature Rev. Mol. Cell Biol. 10, 877–884 (2009).

    CAS  Article  Google Scholar 

  86. Hurd, D. D. & Saxton, W. M. Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila. Genetics 144, 1075–1085 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Xia, C. H. et al. Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. J. Cell Biol. 161, 55–66 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Gupta, V., Palmer, K. J., Spence, P., Hudson, A. & Stephens, D. J. Kinesin-1 (uKHC/KIF5B) is required for bidirectional motility of ER exit sites and efficient ER-to-Golgi transport. Traffic 9, 1850–1866 (2008).

    CAS  PubMed  Article  Google Scholar 

  89. Schüle, R. et al. SPG10 is a rare cause of spastic paraplegia in European families. J. Neurol. Neurosurg. Psychiatry 79, 584–587 (2008).

    PubMed  Article  Google Scholar 

  90. Ebbing, B. et al. Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. Hum. Mol. Genet. 17, 1245–1252 (2008).

    CAS  PubMed  Article  Google Scholar 

  91. Kurth, I. et al. Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy. Nature Genet. 41, 1179–1181 (2009).

    CAS  PubMed  Article  Google Scholar 

  92. McCray, B. A., Skordalakes, E. & Taylor, J. P. Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation. Hum. Mol. Genet. 19, 1033–1047 (2010).

    CAS  PubMed  Article  Google Scholar 

  93. Yang, Y. S., Harel, N. Y. & Strittmatter, S. M. Reticulon-4A (Nogo-A) redistributes protein disulfide isomerase to protect mice from SOD1-dependent amyotrophic lateral sclerosis. J. Neurosci. 29, 13850–13859 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Fasana, E. et al. A VAPB mutant linked to amyotrophic lateral sclerosis generates a novel form of organized smooth endoplasmic reticulum. FASEB J. 24, 1419–1430 (2010).

    CAS  PubMed  Article  Google Scholar 

  95. Chen, K. M., Brody, J. A. & Kurland, L. T. Patterns of neurologic diseases on Guam. Arch. Neurol. 19, 573–578 (1968).

    CAS  PubMed  Article  Google Scholar 

  96. Erichsen, A. K., Koht, J., Stray-Pedersen, A., Abdelnoor, M. & Tallaksen, C. M. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain 132, 1577–1588 (2009).

    PubMed  Article  Google Scholar 

  97. Harding, A. E. Classification of the hereditary ataxias and paraplegias. Lancet 1, 1151–1155 (1983).

    CAS  PubMed  Article  Google Scholar 

  98. Silva, M. C., Coutinho, P., Pinheiro, C. D., Neves, J. M. & Serrano, P. Hereditary ataxias and spastic paraplegias: methodological aspects of a prevalence study in Portugal. J. Clin. Epidemiol. 50, 1377–1384 (1997).

    CAS  PubMed  Article  Google Scholar 

  99. Nielsen, J. E. et al. Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation. Eur. J. Neurol. 11, 817–824 (2004).

    CAS  PubMed  Article  Google Scholar 

  100. Hierro, A. et al. Functional architecture of the retromer cargo-recognition complex. Nature 449, 1063–1067 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Zhao, X. et al. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nature Genet. 29, 326–331 (2001).

    CAS  PubMed  Article  Google Scholar 

  102. Rainier, S., Chai, J. H., Tokarz, D., Nicholls, R. D. & Fink, J. K. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am. J. Hum. Genet. 73, 967–971 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Stevanin, G. et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nature Genet. 39, 366–372 (2007).

    CAS  PubMed  Article  Google Scholar 

  104. Hanein, S. et al. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am. J. Hum. Genet. 82, 992–1002 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Sagona, A. P. et al. PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody. Nature Cell Biol. 12, 362–371 (2010).

    CAS  PubMed  Article  Google Scholar 

  106. Windpassinger, C. et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nature Genet. 36, 271–276 (2004).

    CAS  PubMed  Article  Google Scholar 

  107. Patel, H. et al. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nature Genet. 31, 347–348 (2002).

    CAS  PubMed  Article  Google Scholar 

  108. Simpson, M. A. et al. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am. J. Hum. Genet. 73, 1147–1156 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Züchner, S. et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am. J. Hum. Genet. 79, 365–369 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  110. Hansen, J. J. et al. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am. J. Hum. Genet. 70, 1328–1332 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).

    CAS  PubMed  Article  Google Scholar 

  112. Saugier-Veber, P. et al. X-linked spastic paraplegia and Pelizaeus–Merzbacher disease are allelic disorders at the proteolipid protein locus. Nature Genet. 6, 257–262 (1994).

    CAS  PubMed  Article  Google Scholar 

  113. Dick, K. J. et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum. Mutat. 31, E1251–E1260 (2010).

    CAS  PubMed  Article  Google Scholar 

  114. Edvardson, S. et al. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am. J. Hum. Genet. 83, 643–648 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Jouet, M. et al. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nature Genet. 7, 402–407 (1994).

    CAS  PubMed  Article  Google Scholar 

  116. Tsaousidou, M. K. et al. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am. J. Hum. Genet. 82, 510–515 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Read, D. J., Li, Y., Chao, M. V., Cavanagh, J. B. & Glynn, P. Neuropathy target esterase is required for adult vertebrate axon maintenance. J. Neurosci. 29, 11594–11600 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Lin, P. et al. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am. J. Hum. Genet. 83, 752–759 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Slabicki, M. et al. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 8, e1000408 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the members of our laboratories who have contributed to HSP-related work, and to the many HSP family members who have helped with our research. We thank T. Wahlig and H. Wahlig for their tireless work in promoting interactions among HSP researchers, clinicians and families. E.R. is a Wellcome Trust Senior Research Fellow in Clinical Science (grant 082381) and is also supported by the UK Medical Research Council, the Tom Wahlig Stiftung and the UK HSP Support Group. The work of C.J.O'K. on HSP is funded by Wellcome Trust (grant WT081386). C.B. is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, US National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Evan Reid.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Craig Blackstone's homepage

Cahir J. O'Kane's homepage

Evan Reid's homepage

Glossary

Upper motor neurons

Neurons whose fibres comprise descending pathways in the CNS and that are involved in voluntary control of skeletal muscle contraction. Corticospinal neurons are a type of upper motor neuron.

Decussate

To cross the midline to reach the contralateral side of the nervous system.

Paraplegia

Muscle weakness involving both legs.

Spasticity

Increased muscle tone and deep tendon reflexes resulting from damage to the corticospinal tract.

Protomer

A structural unit of an oligomeric protein.

Early secretory pathway

A pathway through the endoplasmic reticulum (ER), ER-to-Golgi intermediate compartment and the cis-Golgi apparatus.

Viral budding

The process by which an enveloped virus particle is released from the plasma membrane of a host cell.

Abscission

The final stage of cytokinesis, when the midbody connecting two daughter cells is broken and sealed.

Cytokinesis

The stage in cell division when the cytoplasm of a single cell is divided to form two daughter cells.

Midbody

The tubular plasma membrane-bound structure that connects two daughter cells in the late stage of cytokinesis.

Anti-parallel

Running side-by-side, but in opposite directions. A bundle of microtubules is anti-parallel if the microtubules of which it is comprised have plus ends facing both directions.

Paralogues

Similar DNA and protein sequences (often distinct genes) within a species.

Hydrophobic wedging

A mechanism for inducing membrane curvature by partitioning the bulk of a hydrophobic domain within the outer leaflet of the bilayer.

Tubular transport intermediates

Membrane-bound, small, cigar-shaped organelles that are trafficked from one intracellular membrane compartment to another. They are distinguished by their shape from vesicular transport intermediates, which are spherical.

Polytopic integral membrane protein

A protein that spans the membrane more than once because it has more than one transmembrane domain.

Clathrin-mediated endocytosis

The major endocytic pathway, in which cells internalize extracellular or plasma membrane molecules into clathrin-coated vesicles. Once uncoated, the vesicles are capable of fusing with internal organelles, such as endosomes.

Unfolded protein response

A cellular stress response that is triggered by excess of unfolded or misfolded proteins in the endoplasmic reticulum.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Blackstone, C., O'Kane, C. & Reid, E. Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci 12, 31–42 (2011). https://doi.org/10.1038/nrn2946

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2946

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing