Review
Molecular basis of inherited spastic paraplegias

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Abstract

Recently, paraplegin and spastin have been found to be mutated in two autosomal forms of hereditary spastic paraplegia. Both proteins harbour a common ATPase domain that expresses a chaperone function. Paraplegin is a nuclear-encoded mitochondrial metalloprotease, while the exact role and subcellular localisation of spastin are still unclear.

Introduction

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of disorders characterised by progressive lower-limb weakness and spasticity, with or without bladder disturbances, and subtle impairment of the vibratory sense 1., 2., 3.. Age of onset is quite variable — generally between 10 and 40 years old. First described by Strumpell in 1880, HSP has been classified traditionally as ‘pure’ or ‘complicated’, depending on whether spastic paraplegia is the only symptom or whether it is found in association with other neurological abnormalities, such as optic neuropathy, retinopathy, extrapyramidal symptoms, dementia, ataxia, mental retardation and deafness [4].

Neuropathological analyses of tissues from a small number of individuals with pure HSP have shown axonal degeneration involving the more distal portions of the longest motor and sensory axons of the central nervous system (CNS) (i.e. the crossed and uncrossed corticospinal tracts, the fasciculus gracilis and the spinocerebellar tracts) 5., 6.. These studies showed that the neuronal cell bodies of the degenerating axons are intact; no degeneration of the dorsal root ganglia, dorsal roots or peripheral nerves was found, and there was no evidence of primary demyelination. The pathogenetic mechanism for this ‘dying back’ axonopathy and why it is confined to defined axonal tracts is still unknown and represents an engaging biological question.

HSP is a genetically heterogeneous condition that can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner [7]. So far, 15 loci have been mapped (known as SPG1–SPG15, see Table 1), but only four genes have been cloned so far. These encode L1 cell adhesion molecule (L1CAM), proteolipid protein (PLP), paraplegin and spastin. L1CAM and PLP are responsible for two X-linked complicated forms of HSP, paraplegin is involved in autosomal recessive pure and complicated HSP, and spastin is mutated in most autosomal dominant cases. In this review. we will focus on the most recent advances in understanding the molecular pathogenesis of HSP, and will discuss novel findings involving these known HSP genes. This research has stimulated an understanding of several different aspects of the biology of corticospinal axons and highlights the relevance of distinct — and possibly interconnected — pathways for pathogenesis of HSP.

Section snippets

HSP caused by impaired development of the corticospinal tract

SPG1 results from mutations in L1CAM [8], and may manifest as pure HSP or, more often, in association with complex disorders, referred to either as MASA syndrome (mental retardation, adducted thumbs, spasticity and aphasia) or CRASH syndrome (corpus callosum hypoplasia, mental retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) [9]. L1CAM is a transmembrane glycoprotein with extracellular immunoglobulin and fibronectin type III repeats [10]. It is expressed during development

HSP caused by perturbation of axonal–glial interactions

SPG2 maps to Xq22 and results from mutations in PLP, one of the major protein components of myelin in the CNS. PLP and its splicing variant DM20 (an isoform of PLP originating from alternative splicing of the same gene) are four-helix-spanning membrane proteins thought to stabilise the structure of the CNS myelin by forming the intraperiod line. SPG2 comprises both pure and complicated forms of HSP, and is allelic to Pelizaeus–Merzbacher disease (PMD) [20]. PMD is characterised by significant

Paraplegin and mitochondria in HSP

The successful identification of the first autosomal determinant of HSP resulted from genome-wide linkage mapping followed by positional candidate selection. The 6 cM critical region on chromosome 16 identified as being affected by a pure form of HSP harboured many genes and partial transcripts [27]. We focused on an expressed sequence tag (EST) (which, we learnt later, was part of the SPG7 cDNA, coding for paraplegin) similar to yeast mitochondrial genes. Using a set of primers designed to

Spastin, a new AAA protein, is responsible for 40% of autosomal dominant HSP

In 1999, the gene responsible for the most frequent form of autosomal dominant spastic paraplegia, SPG4, previously mapped to chromosome 2p 37., 38., was identified and found to encode a 616-amino-acid protein, called spastin [39••]. Cloning of the disease gene was aided by the finding of an EST that mapped to the SPG4 critical interval and had homology to genes encoding proteins of the AAA family. The AAA domain is localised in the C-terminal part of spastin, between amino acid 342 and 599 and

Conclusions

The specificity of the axonal damage in HSP apparently contrasts with the wide distribution and range of functions carried out by the few gene products known to cause the clinical phenotypes. The picture emerging from the most recent research indicates that both normal development and homeostasis of corticospinal axons are necessary to prevent degeneration (Fig. 2). The integrity of the long corticospinal axons is maintained through extrinsic factors, such the myelin protein PLP, and intrinsic

Acknowledgements

We thanks Peter Byers for a critical reading of the manuscript. We also wish to thank the Italian Telethon Foundation, the Italian Minister of Health, and MURST.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

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  • •• of outstanding interest

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