Abstract
SummaryThe Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body. Owing to the combination of genetic diversity and variable clinical presentation, the Hereditary Spastic Paraplegias are a strong candidate for protein-protein interaction network analysis as a tool to understand disease mechanism(s) and to aid functional stratification of phenotypes. In this study, experimentally validated human data were used to create a protein-protein interaction network based on the causative genes. Network evaluation as a combination of topological analysis and functional annotation led to the identification of core proteins in putative shared biological processes, such as intracellular transport and vesicle trafficking. The application of machine learning techniques suggested a functional dichotomy linked with distinct sets of clinical presentations, indicating that there is scope to further classify conditions currently described under the same umbrella-term of Hereditary Spastic Paraplegias based on specific molecular mechanisms of disease.
Highlights
The Hereditary Spastic Paraplegias (HSPs) are a group of heterogeneous neurodegenerative diseases characterized by the core features of slowly progressive bilateral lower limb spasticity, hyperreflexia, and extensor plantar responses (Harding, 1983) accompanied by degeneration of the upper motor neurons (Deluca et al, 2004)
SUMMARY The Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body
Owing to the combination of genetic diversity and variable clinical presentation, the Hereditary Spastic Paraplegias are a strong candidate for protein-protein interaction network analysis as a tool to understand disease mechanism(s) and to aid functional stratification of phenotypes
Summary
The Hereditary Spastic Paraplegias (HSPs) are a group of heterogeneous neurodegenerative diseases characterized by the core features of slowly progressive bilateral lower limb spasticity, hyperreflexia, and extensor plantar responses (Harding, 1983) accompanied by degeneration of the upper motor neurons (Deluca et al, 2004). The heterogeneity of the HSPs derives from both the complex range of clinical presentations (summarized in Table S1) and diverse underlying genetic causes Regarding the former, the age of onset can vary from early childhood to late adulthood, all modes of inheritance can be observed, and the form of the disease can be pure or complex. Regarding the genetic heterogeneity of HSPs, mutations in over 70 genes have been associated with the HSPs (Faber et al, 2017), rendering it one of the hereditary disorders with the highest numbers of known causative genes (Blackstone, 2018a) In such a complex scenario, it is not clear as to whether all the HSP syndromes, despite being classified under the same umbrella term, share the same underlying molecular etiology (Blackstone, 2018a). Given the lack of treatments able to prevent, halt, or revert the HSPs, understanding the etiology of these disorders and gaining greater clarity in this area of HSP biology is crucial
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