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Integrating protein networks and machine learning for disease stratification in the Hereditary Spastic Paraplegias

By Nikoleta Vavouraki, James E Tomkins, Eleanna Kara, Henry Houlden, John Hardy, Marcus J. Tindall, Patrick A Lewis, Claudia Manzoni

Posted 16 Jan 2021
bioRxiv DOI: 10.1101/2021.01.14.425874

The Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body. Despite the identification of causative mutations in over 70 genes, the molecular aetiology remains unclear. Due 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 protein-protein interactions were used to create a protein-protein interaction network based on the causative Hereditary Spastic Paraplegia genes. Network evaluation as a combination of both 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, suggesting 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.

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