Chapter 228.1

## Abstract

Abstract

1. Hereditary spastic paraplegias (HSPs) are genetic conditions in which the cardinal clinical feature is a slowly progressive weakness and spasticity of the lower limbs. Historically, they have been divided into pure and complicated forms. Complicated forms are characterized by the presence of additional neurological and non-neurological symptoms, such as cerebral and cerebellar atrophy, optic atrophy, peripheral neuropathy, retinitis pigmentosa, deafness, dementia, amyotrophy, and ichthyosis. Age at onset is variable and can range from childhood to adult life. The prevalence of these diseases has been estimated between 1 and 18.4 cases per 100,000 individuals.

2. The characteristic neuropathological feature of most HSPs is a progressive length-dependent distal axonopathy, mainly affecting the lateral corticospinal tracts, but also affecting to a lesser extent the anterior corticospinal tracts, the spinocerebellar tracts and the dorsal columns. The cell bodies of affected axons, such as Betz cells in the motor cortex, are relatively spared.

3. HSPs are genetically heterogeneous. Autosomal dominant, autosomal recessive and X-linked forms have been recognized. At the time of writing, almost 40 HSP loci have been mapped with 18 genes identified. Autosomal dominant inheritance accounts for about 70-80% of all HSP cases in Northern Europe and America, and is predominantly associated with pure forms. Most complicated HSPs are inherited as autosomal recessive traits. Knowledge of the molecular bases of HSPs has indicated that the distinction between pure and complicated forms is frequently blurred. Moreover, genes implicated in HSP can be responsible of other neurodegenerative phenotypes.

4. Despite the molecular complexity of HSPs, common pathogenic themes are emerging from functional studies of the genes. The proteins encoded by HSP genes fall into two main categories: proteins involved in intracellular membrane trafficking, and mitochondrial quality control. These pathways may be particularly crucial for maintenance of the long corticospinal axons, which can reach the length of 1 m in humans, contain 99% of the cytoplasm of the cell, and are strictly dependant on efficient transport mechanisms.

5. Three genes, SPG4 encoding for spastin, SPG3A encoding for atlastin, and SPG31 encoding for REEP1, seem to function in a common pathway, involving endoplasmic reticulum (ER) morphogenesis. Spastin is a microtubule-severing protein implicated in membrane trafficking processes that require microtubule modeling. Spastin directly interacts with atlastin, a large GTPase that mediates homotypic ER membrane fusion. In turn, atlastin interacts with DP1 protein family members, required for efficient formation of ER tubules, one of which is REEP1.

6. A group of HSP proteins, including spastin, NIPA1, and spartin, have an endosomal localization. These three proteins appear to have a role in endosomal trafficking, and all three function as negative regulators of bone morphogenetic protein (BMP) signaling.

7. A second class of HSP proteins localize to mitochondria. The prototype of these proteins is paraplegin, a metalloprotease of the inner mitochondrial membrane. Paraplegin assembles with the homologous protein AFG3L2 to form the m-AAA protease, a proteolytic complex involved in quality control of inner mitochondrial membrane proteins and in processing of regulatory proteins. The implication of a mitochondrial matrix chaperone, the heat shock protein 60, in HSP further underlines the role of mitochondrial quality control in this disease.

8. Mouse models have been developed for three HSP proteins, the microtubule-severing protein spastin, the mitochondrial metalloprotease paraplegin, and the myelin component PLP1. Despite the seemingly diverse functional roles of the individual proteins, the phenotype of these mice is remarkably similar, and is characterized by late-onset distal axonal degeneration with swellings accumulating organelles and cytoskeletal components. In all cases, impaired axonal transport has been demonstrated, suggesting that this may be the common final mechanism mediating axonal degeneration.

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