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.
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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Goldstein, A. Y., Wang, X. & Schwarz, T. L. Axonal transport and the delivery of pre-synaptic components. Curr. Opin. Neurobiol. 18, 495–503 (2008).
Harding, A. E. The Hereditary Ataxias and Related Disorders (Churchill Livingston, Edinburgh, 1984).
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).
Fischer, L. R. et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185, 232–240 (2004).
Harding, A. E. Hereditary spastic paraplegias. Semin. Neurol. 13, 333–336 (1993).
Fink, J. K. Hereditary spastic paraplegia. Curr. Neurol. Neurosci. Rep. 6, 65–76 (2006).
McDermott, C. J. & Shaw, P. J. Hereditary spastic paraplegia. Int. Rev. Neurobiol. 53, 191–204 (2002).
Reid, E. The hereditary spastic paraplegias. J. Neurol. 246, 995–1003 (1999).
Salinas, S., Proukakis, C., Crosby, A. & Warner, T. T. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol. 7, 1127–1138 (2008).
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).
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.
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).
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).
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).
Roll-Mecak, A. & McNally, F. J. Microtubule-severing enzymes. Curr. Opin. Cell Biol. 22, 96–103 (2010).
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).
White, S. R. & Lauring, B. AAA+ ATPases: achieving diversity of function with conserved machinery. Traffic 8, 1657–1667 (2007).
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.
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.
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.
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.
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.
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).
Hurley, J. H. ESCRT complexes and the biogenesis of multivesicular bodies. Curr. Opin. Cell Biol. 20, 4–11 (2008).
Raiborg, C. & Stenmark, H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445–452 (2009).
Slagsvold, T., Pattni, K., Malerod, L. & Stenmark, H. Endosomal and non-endosomal functions of ESCRT proteins. Trends Cell Biol. 16, 317–326 (2006).
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).
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).
Agromayor, M. et al. Essential role of hIST1 in cytokinesis. Mol. Biol. Cell 20, 1374–1387 (2009).
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).
Piel, M., Nordberg, J., Euteneuer, U. & Bornens, M. Centrosome-dependent exit of cytokinesis in animal cells. Science 291, 1550–1553 (2001).
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).
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).
Carlton, J. G. & Martin-Serrano, J. Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery. Science 316, 1908–1912 (2007).
Riano, E. et al. Pleiotropic effects of spastin on neurite growth depending on expression levels. J. Neurochem. 108, 1277–1288 (2009).
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).
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).
Shirane, M. & Nakayama, K. I. Protrudin induces neurite formation by directional membrane trafficking. Science 314, 818–821 (2006).
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).
Orso, G. et al. Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin. Nature 460, 978–983 (2009).
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).
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).
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).
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).
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).
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).
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).
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.
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).
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).
Insall, R. H. & Machesky, L. M. Actin dynamics at the leading edge: from simple machinery to complex networks. Dev. Cell 17, 310–322 (2009).
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).
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).
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).
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).
Keshishian, H. & Kim, Y. S. Orchestrating development and function: retrograde BMP signaling in the Drosophila nervous system. Trends Neurosci. 27, 143–147 (2004).
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).
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).
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).
Lasorella, A. et al. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 442, 471–474 (2006).
Aberle, H. et al. wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron 33, 545–558 (2002).
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).
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.
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
Daisuke, I. & Norihiro, S. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann. Neurol. 61, 237–250 (2007).
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).
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).
Deng, H. X. et al. Distal axonopathy in an alsin-deficient mouse model. Hum. Mol. Genet. 16, 2911–2920 (2007).
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).
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).
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).
Reid, E. et al. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am. J. Hum. Genet. 71, 1189–1194 (2002).
Goizet, C. et al. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Hum. Mutat. 30, E376–385 (2009).
Hirokawa, N. & Noda, Y. Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol. Rev. 88, 1089–1118 (2008).
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).
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).
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).
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).
Schüle, R. et al. SPG10 is a rare cause of spastic paraplegia in European families. J. Neurol. Neurosurg. Psychiatry 79, 584–587 (2008).
Ebbing, B. et al. Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. Hum. Mol. Genet. 17, 1245–1252 (2008).
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).
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).
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).
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).
Chen, K. M., Brody, J. A. & Kurland, L. T. Patterns of neurologic diseases on Guam. Arch. Neurol. 19, 573–578 (1968).
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).
Harding, A. E. Classification of the hereditary ataxias and paraplegias. Lancet 1, 1151–1155 (1983).
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).
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).
Hierro, A. et al. Functional architecture of the retromer cargo-recognition complex. Nature 449, 1063–1067 (2007).
Zhao, X. et al. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nature Genet. 29, 326–331 (2001).
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).
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).
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).
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).
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).
Patel, H. et al. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nature Genet. 31, 347–348 (2002).
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).
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).
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).
Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).
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).
Dick, K. J. et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum. Mutat. 31, E1251–E1260 (2010).
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).
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).
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).
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).
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).
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).
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.
The authors declare no competing financial interests.
- 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.
To cross the midline to reach the contralateral side of the nervous system.
Muscle weakness involving both legs.
Increased muscle tone and deep tendon reflexes resulting from damage to the corticospinal tract.
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.
The final stage of cytokinesis, when the midbody connecting two daughter cells is broken and sealed.
The stage in cell division when the cytoplasm of a single cell is divided to form two daughter cells.
The tubular plasma membrane-bound structure that connects two daughter cells in the late stage of cytokinesis.
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.
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.
About this article
Nature Structural & Molecular Biology (2019)
Complexity of Generating Mouse Models to Study the Upper Motor Neurons: Let Us Shift Focus from Mice to Neurons
International Journal of Molecular Sciences (2019)
Nature Chemical Biology (2019)
Spastin Contributes to Neural Development through the Regulation of Microtubule Dynamics in the Primary Cilia of Neural Stem Cells
A mouse model for SPG48 reveals a block of autophagic flux upon disruption of adaptor protein complex five
Neurobiology of Disease (2019)