Protein-protein interactions (PPIs) form a complex network called "interactome" that regulates many functions in the cell. In recent years, there is an increasing accumulation of evidence supporting the existence of a hyperbolic geometry underlying the network representation of complex systems such as the interactome. In particular, it has been shown that the embedding of the human Protein-Interaction Network (hPIN) in hyperbolic space (H2) captures biologically relevant information. Here we explore whether this mapping contains information that would allow us to predict the function of PPIs, more specifically interactions related to post-translational modification (PTM). We used a random forest algorithm to predict PTM-related directed PPIs, concretely, protein phosphorylation and dephosphorylation, based on hyperbolic properties and centrality measures of the hPIN mapped in H2. To evaluate the efficacy of our algorithm, we predicted PTM-related PPIs of ataxin-1, a protein which is responsible for Spinocerebellar Ataxia type 1 (SCA1). Proteomics analysis in a cellular model revealed that several of the predicted PTM-PPIs were indeed dysregulated in a SCA1-related disease network. A compact cluster composed of ataxin-1, its dysregulated PTM-PPIs and their common upstream regulators may represent critical interactions for disease pathology. Thus, our algorithm may infer phosphorylation activity on proteins through directed PPIs.

• MeSH
• Algorithms MeSH
• Phosphorylation MeSH
• Humans MeSH
• Protein Interaction Mapping * methods   MeSH
• Protein Interaction Maps * MeSH
• Protein Processing, Post-Translational MeSH
• Proteomics MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder, with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1154Q/2Q and healthy SCA12Q/2Q mice were administered either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation, and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models, combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1.

• Keywords
• cerebellum, edaravone, mitochondria, neurodegeneration, spinocerebellar ataxia type 1,
• MeSH
• Bayes Theorem MeSH
• Edaravone pharmacology   therapeutic use   MeSH
• Cognitive Dysfunction * metabolism   MeSH
• Mitochondria MeSH
• Disease Models, Animal MeSH
• Cerebellum metabolism   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Purkinje Cells MeSH
• Spinocerebellar Ataxias * drug therapy   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Edaravone MeSH