Abstract
Hereditary spastic paraplegia (HSP) and hereditary ataxia (HA) are two groups of disorders characterized, respectively, by progressive dysfunction or degeneration of the pyramidal tracts (HSP) and of the Purkinje cells and spinocerebellar tracts (HA). Although HSP and HA are generally shown to have distinct clinical-genetic profiles, in several cases the clinical presentation, the causative genes, and the cellular pathways and mechanisms involved overlap between the two forms. Genetic analyses in humans in combination with in vitro and in vivo studies using model systems have greatly expanded our knowledge of spinocerebellar degenerative disorders. In this review, we focus on the zebrafish (Danio rerio), a vertebrate model widely used in biomedical research since its overall nervous system organization is similar to that of humans. A critical analysis of the literature suggests that zebrafish could serve as a powerful experimental tool for molecular and genetic dissection of both HA and HSP. The zebrafish, found to be very useful for demonstrating the causal relationship between defect and mutation, also offers a useful platform to exploit for the development of therapies.
Highlights
The term hereditary spastic paraplegia (HSP) refers to a large group of clinically and genetically heterogeneous neurodegenerative diseases, essentially characterized by progressive spasticity and weakness, mainly affecting the lower limbs (Bellofatto et al, 2019; Boutry et al, 2019a; Peng et al, 2019)
The recent technological advances in gene sequencing that allow the analysis of entire genomes of patients affected by neurodegenerative disorders, such as Hereditary spastic paraplegia (HSP) and spastic ataxias (ASS) (Figure 3), have brought rapid developments in terms of the identification of novel genes and potentially pathogenic variants
It clearly emerged that HSP, hereditary ataxia (HA), ataxia-spasticity spectrum (ASS), and other neurological disorders are part of a continuum of overlapping clinical conditions
Summary
The term hereditary spastic paraplegia (HSP) refers to a large group of clinically and genetically heterogeneous neurodegenerative diseases, essentially characterized by progressive spasticity and weakness, mainly affecting the lower limbs (Bellofatto et al, 2019; Boutry et al, 2019a; Peng et al, 2019). The various forms of HSP, as well as the groups of similar neurodegenerative diseases, such as hereditary ataxia (HA), spinocerebellar ataxia (SCA), autosomal-recessive spinocerebellar ataxia (SCAR), and spastic paraplegia, can be due to mutations in either the spastic paraplegia gene (SPG) or the spastic ataxia genes (SPAX) They can present as pure or complicated phenotypes (Synofzik and Schüle, 2017). It is possible that HSP and HA could share certain pathological mechanisms and cellular pathways For all these reasons, a new classification of ataxia-spasticity spectrum (ASS) genes has recently been proposed (Synofzik and Schüle, 2017). To further expand our review, we consider genes classified as part of the ASS spectrum and not routinely included in the formal HSP classifications
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