The Effect of a Spastic Ataxia Associated GBA2 Mutation on Protein-Protein Interactions and Pathways

Spastic ataxia (SA) is a term used to describe a neurodegenerative disorder that is characterised by imbalance and incoordination in gait and limbs, accompanied by spasticity. Recently the GBA2 gene has been reported as an SA associated gene. In 2014, Votsi et al., reported a novel missense mutation (Asp594His) in a Cypriot consanguineous family with SA. However, the pathogenetic mechanism that leads to the development of this disease remains unclear. A multisource-data integration approach developed by our team, was used for the prediction of candidate pathways that may be involved in GBA2-related diseases, including SA. Protein-protein interactions and partnerships are the basis for understanding molecular pathways. Changes in the interaction sites of GBA2 may disrupt allosterically its catalytic activity, related pathway regulation and contribute towards the development of SA. In this work, protein-protein interactions of the wild-type and mutant GBA2 were predicted using a sequence-based predictor tool, called SPRINT, in order to identify loss or gain of protein-protein interactions of the mutant protein. Finally, we performed pathway analysis of the lost or gained protein interactors and the candidate pathways resulting from this study were compared with the ones predicted by our previous multi-source integration approach. Our method aims to discover candidate pathways that may be affected and enhance our understanding of the pathogenetic mechanisms that may underlie the development of SA.