Review Article. Hereditary Spastic Paraplegia: Clues from a Rare Disorder for a Common Problem?

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1 IUBMB Life, 55(6): , June 2003 Review Article Hereditary Spastic Paraplegia: Clues from a Rare Disorder for a Common Problem? Jean-Marc Burgunder 1 and Walter Hunziker 2 1 Department of Medicine, National University of Singapore, and National Neuroscience Institute, Singapore 2 Institute of Cell and Molecular Biology, Singapore Summary Hereditary spastic paraplegia is a rare disorder with gait disturbance due to a degeneration of the corticospinal tract, sometimes accompanied by involvement of other systems. Out of the 20 loci known so far, eight genes have now been identified, allowing the first molecular and cell studies in the pathophysiology of the disorder. These should also help to understand the function of the corticospinal tract at the molecular level and design strategies to prevent and treat spasticity due to more common causes. The proteins encoded by these genes play a role in development, in signal transduction between axons and myelinating cells, in cellular, particularly axonal trafficking or in energy metabolism. Some of them have actions in several areas of cellular function. Here we review the present knowledge about the genes involved in hereditary spastic paraplegia, a field presently undergoing rapid change. IUBMB Life, 55: , 2003 Keywords Hereditary spastic paraplegia; spastin; spartin; atlastin; L1-CAM; PLP1. SPASTICITY AND PARAPLEGIA Spasticity and paraplegia are common symptoms in many frequent neurological disorders, like stroke, inflammation, infection and trauma. Often, only symptomatic treatment can be offered. Many prior studies have been performed to understand the physiological basis of spasticity (1). The molecular mechanisms underlying the development of spasticity after different types of lesions, however, are not well known. Hereditary spastic paraplegia (HSP), particularly in its pure form, where no other major symptoms are found, offers a nature experiment allowing the study of molecular events involved in spasticity. It is suggested, that results stemming Received 1 April 2003; accepted 16 May 2003 Address correspondence to J.-M. Burgunder, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore mdcbjm@nus.edu.sg from studies on the function of genes involved in HSP will promote our knowledge of molecular events found in spasticity in general. This understanding would allow the probing of these genes in cases of spasticity due to other causes, similar to recent developments in the field of Parkinson s disease, for example. In this disorder, the discovery of a-synuclein, even if it has been found mutated only in rare affected families has, nevertheless, greatly increased our understanding of the idiopathic form of the disease, in which this molecule is also involved. Here we review the present status of our understanding of HSP based on new findings of the genes involved. A brief introduction to the disease is followed by an attempt to integrate the partial data already available. We are well aware that the field is presently in steady development, and that new data will certainly change our views again. HEREDITARY SPASTIC PARAPLEGIA Hereditary spastic paraplegia (HSP) is a group of conditions characterized by a steadily progressive spastic gait disorder occurring at different ages and modes of inheritance. HSP may occur in a pure or uncomplicated form with progressive leg spasticity, leading to a gait disorder starting at any age, but mainly between the ages of 20 and 40 years. In the complex forms of the disease, the gait disorder is accompanied by symptoms and signs indicating a more widespread nervous system involvement, including polyneuropathy, optic neuropathy, other movement disorders, epilepsy and dementia, amyotrophy, or even of other organs. So far at least 20 loci have been mapped in different forms of the disorder. Four genes have been found in dominant forms, atlastin (SPG3a), spastin (SPG4), KIF5A (SPG10) and HSP60 (SPG13); two for recessive forms, paraplegin (SPG7) and spartin (SPG20), and two for X chromosomal forms, phospholipoprotein 1 (PLP1, SPG2) and a cell adhesion molecule, L1-CAM (SPG1). Mutations in the spastin gene are by far the most frequent ones and are found in 40% of the families with autosomal ISSN print/issn online # 2003 IUBMB DOI: /

2 348 BURGUNDER AND HUNZIKER Figure 1. Summary of present evidence for the molecular mechanisms leading to degeneration of the corticospinal tract in hereditary spastic paraplegia. dominant, pure form of the disorder, in 9% of them a linkage to the SPG3a locus can be found (2). Linkage to other loci and mutations of other genes are less common, and so far, some have been reported only in individual families. Rare neuropathological descriptions in HSP have demonstrated a degeneration of the corticospinal tract, the fasciculus gracilis and the spinocerebellar tract (3). These include the longest axons found in the central nervous system and degeneration is most severe in their distal portion, while the perikarya were devoid of obvious abnormalities, at least with the techniques used at that time. So far, no information is available to know whether the genes involved in HSP are, indeed, directly expressed in these affected neuronal populations, or whether other mechanisms have to be taken into consideration. However, it is now possible to link different forms of HSP to related schemes of molecular changes underlying the process of dying back axonopathy. SPASTIN AND SPARTIN Spastin, located on chromosome 2, has 17 exons and the full-length cdna sequence is 3263 bp long. Spastin belongs to a group of proteins known as AAA proteins for ATPases associated with diverse cellular activities (4). Functions associated with proteins carrying an AAA domain, which is a conserved 230 AA motif, include protein folding and assembly (i.e., chaperone functions), cell cycle regulation, protein degradation, organelle biogenesis, and vesicle transport. The AAA cassette is located close to the C-terminal portion of spastin, where a large number of mutations have been found. Other domains within the spastin protein include a proline rich domain, which may bind to SH3 domains, and a putative C-terminal PDZbinding motif, suggesting that spastin may interact with proteins containing PDZ domains. PDZ domains are often found in proteins that link transmembrane proteins to the cytoskeleton and serve as platforms for the assembly of signalling complexes. Further domains found in spastin include an ESP domain (first identified in three molecules, End13/Vsp4, SNX15 and PalB), present in the N terminal part (5). This domain has now also been identified in proteins that interact with microtubules (6), leading to the suggestion of renaming this domain to MIT (microtubuleinteracting and trafficking proteins). Spastin, fused to GST, has indeed been reported in abstract form to interact with a and b tubulin, major components of microtubules (7), however, the significance of this interaction is still not well understood. Spastin tagged with a C-terminal myc epitope is found in the cytoplasmatic, but not in the nuclear fraction of cells and is located to perinuclear punctate structures (8). Spastin with a mutation within the AAA domain leads to a disturbance in microtubule interaction. First, it shows a similar localization as wild type spastin during early phases of cell development. Later, however, it relocalizes to filamentous structures where it colocalizes with a-tubulin but not vimentin. This association can be destabilized by nocodazole induced microtubule depolymerization (8). Interaction of spastin with microtubules is modulated by its N-terminal region and leads to microtubule disassembly. Mutations in the AAA domain leading to defective ATPase function, hinder this disassembly (8). A putative nuclear localization signal (position 7 11 of the human spastin) (4) indicates that the protein may localize to the nucleus, at least under particular conditions. Based on immunoblotting using polyclonal antibodies, two isoforms of 75 and 80 dda were found both in human and mouse (9), which may reflect posttranslational modifications of spastin. The protein is found at high levels in the brain and spinal cord but is absent from muscle in the mouse. It is found in the cerebral cortex and striatum, but not in the cerebellum. Immunohistochemistry using the same antibodies localized the protein to motoneurons of the mouse spinal cord, but not to surrounding glial cells (9). SPG4 splicing and frame shift mutations lead to unstable mrnas (10, 11), which are predicted to lead decreased levels of spastin protein. A similar mrna instability has also been described in mutations leading to exon skipping (12). Most of the missense mutations lead to a predicted disruption of the AAA motiv (10, 13). These data all point to haploinsufficiency as the major molecular mechanism involved in HSP due to spastin mutation. They do not suggest a dominant negative effect, like protein accumulation, as found in many other neurodegenerative disorders including Huntington s, Alzheimer s and Parkinson s disease. It remains to be determined, however, whether some mutations may also lead to normal protein levels with a disturbed function.

3 HEREDITARY SPASTIC PARAPLEGIA 349 Recently the locus of Troyer syndrome, a complex form of autosomal recessive HSP, has been mapped to 13q12.3 in an Amish family (14). The gene, SPG20, has nine exons and encodes a 666 amino acid protein, which has been named spartin (spastic paraplegia autosomal recessive Troyer syndrome) (6). The highest levels of spartin expression are found in adipose tissues. All central nervous system regions studied also express this gene, and there are differences between cerebral lobes, with highest levels in the temporal lobe (14). Interestingly, the MIT domain, mentioned above, is conserved between spastin and spartin (6) indicating that the two proteins may share functional properties. Sequence similarities have also been found with mammalian proteins involved in cellular trafficking. Besides spastic paraplegia, patients suffering from Troyer syndrome are affected by a mild developmental delay with short stature, by dysarthria and distal amyotrophy. It will be interesting to see which biological differences between these two molecules with some similarities will account for the profound phenotypic difference between spartin and spastin mutation induced HSP. It may be that the expression of the two genes is different and that spartin is expressed in additional neurons not expressing spastin. This would allow the dissection of the differential involvement of spastin and spartin proteins in corticospinal function. Furthermore, the fact that spartin mutations also lead to developmental disturbances, for which there are no clinical or morphological clues in patients with spastin mutations, points at differential roles of these proteins during maturation of corticospinal projections. It will be interesting to examine, whether amyotrophy is mainly due to a motoneuron malfunction or whether myopathic changes also play a role, since spartin expression is also found in muscle, albeit at low levels. Reasons why specific cell populations are involved in patients with spastin or spartin mutations are not known. One hypothesis would be that only selected neuronal populations express these genes. A mutation would then only lead to malfunction of these neurons, sparing others. Low levels of spastin and spartin expression are found in many other organs, however, the exact anatomy of its expression in the central nervous system is not known. So far, based on immunoblot analyses, spastin protein has been detected in the cortex and striatum but not in the cerebellum. By using immunohistochemistry in order to examine expression at the cellular level, spastin was found in motoneurons of mouse spinal cord (9). However, motoneurons are precisely not affected in HSP due to spastin mutations, so the question of selective involvement remains unsolved. One hypothesis would be that other genes, selectively expressed in some neurons also containing spastin, would interact with spastin. An interaction disorder of such a molecule with spastin would then lead to cellular malfunction in the corticospinal tract. While some data are now available for spastin, the cellular localization of spartin expression has yet to be examined. L1 CELL ADHESION MOLECULE Mutations in the X-linked L1 and PLP1 genes were the first to be identified as a cause of HSP. L1 mutations sometimes cause a pure, but more often, complex form of the disease, which is allelic to the CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia and hydrocephalus) syndrome, previously also called MASA (mental retardation, aphasia, shuffling gait, and adduced thumbs) and is mapped to chromosome Xq28. Different types of L1 mutations have been found, affecting all domains. No clear correlation between molecular findings and the phenotype could be demonstrated, partly due to a great heterogeneity even within single families. The pattern of involvement in this syndrome already suggested that the disease process would affect brain and spinal cord development and the discovery of mutations in L1, a glycoprotein involved in CNS development and previous studies in hereditary hydrocephalus (15), confirmed this (16). The L1 gene has 28 coding and one non-coding exon, neuronal expression is regulated by a neuron restrictive silencing element and associated with the inclusion of two mini exons absent from the non neuronal transcript (15). L1 is a transmenbrane cell adhesion molecule belonging to the immunoglobulin superfamily (IgCAMs), and contains six Ig-like domains linked to five fibronectin type III domains located on the extracellular side (15). L1 is expressed during development on the extracellular surface of the axolemma in growing axon terminals and promotes axonal fasciculation and neurite extension, with both attractive and repellent mechanisms underlying this developmental feature at the molecular level. L1 plays a particular role in corticospinal tract development and one of the major features of the L1 knockout mouse is a disruption of the corticospinal tract crossing to the contralateral site, with a reduction in size of the pyramids. A large number of interacting proteins mediate the L1 functions, including other IgCAM proteins, integrins, laminin, proteoglycan and other extracellular matrix proteins. Sema3A is a repellent factor inhibiting axonal growth that is secondarily deficient in L1 knock-out mice (17). Besides being a binding partner in complexes involving above proteins, L1 acts also as a receptor that transduces extracellular signals to mediate neurite outgrowth. Other functions involve neuronal cell survival and long-term potentiation, which persist after development, probably explaining the fact that there is a gradual worsening in the phenotype due to L1 mutations, in addition to the disturbed development of central nervous system structures. PROTEOLIPID PROTEIN Another X-chromosomal inherited HSP (SPG2), found both in pure and complicated forms, mapped to Xq22, is due to mutations in the central myelin protein, proteolipid protein 1 (PLP1) (18). Point mutations and duplications of the same gene have been found in Pelizaus-Merzbacher disease,

4 350 BURGUNDER AND HUNZIKER characterized by severe hypomyelination of the central nervous system and presenting with psychomotor developmental delay, ataxia, nystagmus, and spasticity with onset in the first year of life. The gene consists of seven exons and is 17 kb long. PLP1 and its isoform DM 20, which is generated by alternative splicing, is the most abundant protein in the CNS. PLP1has a molecular mass of 30 kda and forms a fourhelix-spanning membrane complex with extracellular disufilde bonds and several cytosolic palmytoilation sites. The major function of PLP is thought to confer stability to the myelin structure at the level of the intraperiod line. Recently specific PLP products have been demonstrated as being expressed in the soma of neurons but not in myelin and named somalrestricted, srplp. The pattern of srplp expression suggests additional roles in differentiation and possible plasticity for PLP (19). An autocrine function has also been suggested on the basis of PLP secretion. Spontaneous animal models, such as the jimpy, the myelin synthesis deficient and the rumpshaker mice, have been known for some time, allowing biochemical and morphological examinations (20). Furthermore, knockout mice that do not express any PLP1 have recently been generated and, although their myelin content is severely diminished due to instability (21), they have normal CNS function and life expectancy. However, ultrastructural analysis revealed alterations in the intraperiod line. Later in life, these animals develop axonal degeneration probably related to abnormal axonal transport. Depending on the type of mutation, several mechanisms have been advanced to explain the myelin formation disorder. Increased or structurally altered PLP1 due to duplications or specific mutations has been suggested to impair intracellular trafficking and metabolism of the protein, resulting in subsequent oligodendrocyte malfunction. Furthermore, alterations of the unfolded protein response, a pathway linking protein trafficking to transcriptional and translational control, have been recently demonstrated in the above spontaneous mouse models as well as in fibroblasts with PLP1 mutations (22). The pattern of axonal involvement after PLP1 mutations is clearly dependent on axonal length, and a length-dependent axonal degeneration has been demonstrated in PLPI null mice and in patients with PLP1 deficiency (23). In addition to the well-known changes in myelin function, developmental abnormalities may be subtle ones, as well as processes within neurons themselves which are now suggested to play a role in the pathogenesis of PLP1 induced neurodegeneration. PARAPLEGIN AND HEAT SHOCK PROTEIN 60 Another form of the disease, inherited as an autosomal recessive trait and presenting as pure paraplegia or associated with other symptoms in a complex form, is linked to SGP7 on chromosome 16q. In the complex form, some features like optic disk pallor, axonal neuropathy and vascular-like lesions suggested some relationship with mitochondrial disorders. The SGP7 gene encodes for paraplegin, a mitochondrial protein with similarity to yeast mitochondrial genes (24). Mutations in this gene are found in 10% of sporadic and recessive HSP cases, and most of them lead to a loss of paraplegin function. Some of the patients with paraplegin induced HSP show other signs of mitochondrial energy impairment, like ragged-red and cytochrome-c oxidase negative muscle fibres with mitochondrial accumulation in their muscle biopsy. Paraplegin also contains an AAA domain with a Walker-type ATP-binding motif. The presence of a zinc-dependent binding domain further suggests a function as a AAA metalloprotease. Mitochondrial AAA proteins are suggested to play a role as chaperones, for example facilitating the association of different proteins involved in the respiratory chain. Heat shock protein 60 (Hsp60, chaperone 60) is also a nuclear encoded mitochondrial protein having recently been found to be mutated in a pure form of HSP, linked to chromosome 2q (SPG13) (25). A mutation in Hsp60 lead to the loss of its chaperone function as demonstrated in an elegant complementation assay in which mutated, in contrast to wild type chaperone 60, failed to rescue a deleted chaperonin gene in Escherichia coli (25). Complex HSP sometimes shows similarities to mitochondrial cytopathies due to mutations in mitochondrial encoded genes and is, therefore, often entertained in the differential diagnosis of the disorder. The finding that mutations of nuclear encoded mitochondrial proteins gives rise to a similar phenotype is, therefore, not surprising. However, reasons for the selective or more pronounced involvement of the corticospinal tract after chaperone 60 and paraplegin mutations remain unclear. ATLASTIN AND KINESIN The protein encoded by SPG3A was named atlastin and is encoded by a gene containing 14 exons. It is highly expressed in the regions of the brain studied so far, including the cortex, while expression in other organs is much lower (26). Atlastin has a molecular mass of 63.4 kd and contains three conserved motives, a P-Loop, DxxG and RD, typical for guanylate binding/gtpase activity sites. Described mutations in atlastin act in a dominant way and are predicted to be located in the conserved GTPase domain, altering the amino acid sequence of the surface of a globular portion of the N-terminal site of the protein (26). The highest sequence similarity is with guanylate binding protein 1 (GBP1) a member of the dynamin family. Dynamins are molecules, which assemble into large polymers to form helical complexes. Beside their role in the formation of clathrin coated vesicles during endocytosis (27), they are essential for other cellular processes requiring vesicular membrane trafficking. Several modes of action have been suggested for these proteins, based either on a mechanochemical or a regulatory fuction of the GTPase. Recent evidence indicates that dynamins may process diverse regulatory functions, while at the same time link the actin

5 HEREDITARY SPASTIC PARAPLEGIA 351 cyoskeleton to cellular membranes, thus acting as polymeric contractile scaffolds (28). At least some dynamin family members are widely expressed in mature neurons and are associated with membranous organelles (29). In contrast, neither the precise subcellular localization of atlastin, not its actual function, are known. A mutation in a kinesin heavy chain gene, KIF5A, has recently been found in a family with HSP linked to chromosome 12q (SPG10) (30). Not all families linked to this locus, however, show mutations in this gene (30). Kinesins are cellular motors associated with microtubules that, in neurons, function in anterograde axonal transport (31). CONCLUSION Several molecular patterns have already emerged from recent knowledge about genes involved in HSP, which allows for the summarization of the molecular pathophysiology of the disorder along some major lines of evidence (Fig. 1). The first one is related to the development of the corticospinal tract. Disturbed development of this structure is quite evident and early in some cases of L1, atlastin or PLP1 mutations. However, more subtle effects on development, due to other mutations of the same genes, or due to some in other genes known or yet to be discovered as being involved in HSP, could remain undetected and only be manifested after secondary process during ageing or accumulating environmental influences. The fact that some of these genes, like spastin, seem to be already expressed early in development, is indeed quite suggestive of such a role. Spasticity is a common symptom in acquired myelin disorders like multiple sclerosis, it is therefore, not surprising that mutations of gene encoding the most common protein involved in CNS myelin formation, PLP1, would cause similar symptoms. A third line is found in the disturbed energy metabolism due to mutations of nuclear encoded mitochondrial proteins, paraplegin and chaperonin 60. Finally the more novel integrating aspect of the molecular pathophysiology of HSP is found in the fact that a number of proteins encoded by involved genes, play major roles in intracellular trafficking. Of course, all these disturbances are expected to affect longer axons more than shorter ones. Even if there are still contradictory findings concerning the exact cellular expression of spastin, a function in microtubular assembly seems already quite well established. For other genes, including atlastin, spartin and KIF5A, a role in cellular trafficking can be assumed from sequence similarities with known proteins involved in such function. The fact that the longest axons are involved first and remain so more severely during the course of the disease, is well established and molecular findings may now be used to explain this phenomenon. Longer axons are more prone to be misdirected during development. Their energy demand is higher and any problem in trafficking is expected to have a more profound impact, which would have a gradient with distal portions more affected than proximal ones. Long axons also bear a much greater cellular membrane surface interacting with the extracellular environment. A clear-cut length dependence of axonal degeneration has recently been demonstrated in human and animals with PLP1 mutations. Major questions remain open, until a more comprehensive and integrating understanding of the molecular pathophysiology of HSP can be put forward. For example, while the perikaryia of the spinal cord motoneurons, which possess the longest axons, do express spastin, no dysfunction of motoneurons is found in patients with HSP due to spastin. Another issue is the great phenotypic variety found in families with individual mutations, for example for the spastin gene. In a cohort of families in central Switzerland with a pure form of HSP due to a single spastin mutation, we have observed patients with a gait disorder already present at the time of gait acquisition, while other were asymptomatic until their seventies. This cannot be explained by differences in environmental influence, since most of the patients live in similar life and work conditions. One of the next tasks, in addition to the search for additional genes involved in HSP, will be to examine the reasons for this phenotypic variability. Modifying genes may play a role, among them we may find polymorphisms in other genes mutated in HSP or in some other interacting partners which still need to be discovered. The identification of new causative and modifying genes is likely to provide additional insight into the molecular mechanisms involved in HSP, as well as in the function of the corticospinal tract in a general sense. Hopefully this will lead to more rational measures to possibly prevent the development of spasticity after lesions of the spinal cord, and to treat spasticity once established. REFERENCES 1. Leon, F., and Dimitrijyevic, M. (1997) Recent concepts in the pathophysiology and evaluation of spasticity. Invest. Clin. 38, Fink, J. K., Heiman-Patterson, T., Bird, T., Cambi, F., Dube, M. P., Figlewicz, D. A., Fink, J. K., Haines, J. L., Heiman-Patterson, T., Hentati, A., et al. (1996) Hereditary spastic paraplegia: advances in genetic research. Hereditary Spastic Paraplegia Working group. Neurology 46, Schwarz, G., and Liu, C.-N. (1956) Hereditary (familial) spastic paraplegia: further clinical and pathological observations. Arch. Neurol. Psychiatry 75, Hazan, J., Fonknechten, N., Mavel, D., Paternotte, C., Samson, D., Artiguenave, F., Davoine, C. S., Cruaud, C., Durr, A., Wincker, P., et al. (1999) Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat. Genet. 23, Crosby, A., and Proukakis, C. (2002) Is the transportation highway the right road for hereditary spastic paraplegia? Am. J. Hum. Genet. 71,

6 352 BURGUNDER AND HUNZIKER 6. Ciccarelli, F. D., Proukakis, C., Patel, H., Cross, H., Azam, S., Patton, M. A., Bork, P., and Crosby, A. H. (2003) The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Genomics 81, Azim, A., Hentati, Q., Haque, M., Hirano, M., Ouachi, K., and Siddique, T. (2000) Spastin, a new AAA protein, binds to a and b tubulins. Am. J. Hum. Genet. 67(suppl), Errico, A., Ballabio, A., and Rugarli, E. I. (2002) Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum. Mol. Genet. 11, Charvin, D., Cifuentes-Diaz, C., Fonknechten, N., Joshi, V., Hazan, J., Melki, J., and Betuing, S. (2003) Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. Hum. Mol. Genet. 12, Fonknechten, N., Mavel, D., Byrne, P., Davoine, C. S., Cruaud, C., Boentsch, D., Samson, D., Coutinho, P., Hutchinson, M., McMonagle, P., et al. (2000) Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum. Mol. Genet. 9, Svenson, I. K., Ashley-Koch, A. E., Pericak-Vance, M. A., and Marchuk, D. A. (2001) A second leaky splice-site mutation in the spastin gene. Am. J. Hum. Genet. 69, Burger, J., Fonknechten, N., Hoeltzenbein, M., Neumann, L., Bratanoff, E., Hazan, J., and Reis, A. (2000) Hereditary spastic paraplegia caused by mutations in the SPG4 gene. Eur. J. Hum. Genet. 8, Proukakis, C., Auer-Grumbach, M., Wagner, K., Wilkinson, P. A., Reid, E., Patton, M. A., Warner, T. T., and Crosby, A. H. (2003) Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene. Hum. Mutat. 21, Patel, H., Cross, H., Proukakis, C., Hershberger, R., Bork, P., Ciccarelli, F. D., Patton, M. A., McKusick, V. A., and Crosby, A. H. (2002) SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat. Genet. 31, Kenwrick, S., Watkins, A., and De Angelis, D. (2000) Neural cell recognition molecule L1: relating biologcial complexity to human disease mutations. Hum. Mol. Gen. 9, Jouet, M., Rosenthal, A., Armstrong, G., MacFarlane, J., Stevenson, R., Paterson, J., Metzenberg, A., Ionasescu, V., Temple, K., and Kenwrick, S. (1994) X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat. Genet. 7, Castellani, V., Chedotal, A., Schachner, M., Faivre-Sarrailh, C., and Rougon, G. (2000) Analysis of the L1-deficient mouse phentype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 27, Saugier-Veber, P., Munnich, A., Bonneau, D., Rozet, J. M., Le Merrer, M., Gil, R., and Boespflug-Tanguy, O. (1994) X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat. Genet. 6, Campagnoni, A. T., and Skoff, R. P. (2001) The pathobiology of myelin mutants reveal novel bological functions of the MBP and PLP genes. Brain Pathol. 11, Yool, D., Edgar, J. M., Mantague, P., and Malcolm, S. (2000) The proteolipid protein gene and myelin disorders in man and animal models. Hum. Mol. Genet. 9, Jurevics, H., Hostettler, J., Sammond, D. W., Nave, K.-A., Toews, A. D., and Morell, P. (2003) Normal metabolism but different physical properties of myelin from mice deficient in proteolipid protein. J. Neurosci. Res. 71, Southwood, C. M., Garbern, J., Jiang, W., and Gow, A. (2002) The unfolded protein response modulates disease severity in Pelizaeus- Merzbacher disease. Neuron 36, Garbern, J. Y., Yool, D. A., Moore, G. J., Wilds, J. B., Faulk, M. W., Klugman, M., Nave, K.-A., Sistermans, E. A., van der Knaap, M. S., Bird, T. D., et al. (2002) Patients lacking the majore CNS myelin protein proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 125, Casari, G., De, F. M., Ciarmatori, S., Zeviani, M., Mora, M., Fernandez, P., De, M. G., Filla, A., Cocozza, S., Marconi, R., et al. (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, Hansen, J. J., Durr, A., Cournu-Rebeix, I., Georgopoulos, C., Ang, D., Nielsen, M. N., Davoine, C. S., Brice, A., Fontaine, B., Gregersen, N., et al. (2002) Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am. J. Hum. Genet. 70, Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber, C. H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., et al. (2001) Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat. Genet. 29, Conner, S. D., and Schmid, S. L. (2003) Regulated portals of entry into the cell. Nature 422, Orth, J. D., and McNiven, M. A. (2003) Dynamin at the actinmembrane interface. Curr. Opin. Cell. Biol. 15, Noda, Y., Nakata, T., and Hirokawa, N. (1993) Localization of dynamin: despread distribution in mature neurons and association with membranous organelles. Neuroscience 55, Reid, E., Kloos, M., Ashley-Koch, A., Hughes, L., Bevan, S., Svenson, I. K., Graham, F. L., Gaskell, P. C., Dearlove, A., Pericak- Vance, M. A., et al. (2002) A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am. J. Hum. Genet. 71, Vale, R. D. (2003) The molecular motor toolboxc for intracellular transport. Cell 112,