Abstract

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, Huntington's disease (HD) or spinal cerebellar ataxias are progressive brain disorders characterised by the accumulation of insoluble protein aggregates in neurons and the extracellular space. To elucidate potential common pathological mechanisms in NDs, we created comprehensive interaction networks for various known neurodegenerative disease proteins (NDPs). Using an automated yeast two-hybrid system, we identified 16 353 protein-protein interactions for 449 bioinformatically selected target proteins, connecting 80 known NDPs. This information was used to generate networks for individual NDs such as AD or PD and to predict proteins that are connected to multiple NDs. We found, for example, that the diseases AD, PD, amyotrophic lateral sclerosis, HD, and spinal cerebellar ataxia 1 are connected via four proteins that link known NDPs such as huntingtin, TDP43, parkin, τ, ataxin-1 and SOD1. Analysis of gene expression data predicted that these four proteins are abnormally altered in brains of HD, PD, and AD patients, supporting their importance for disease pathogenesis. Moreover, utilising computational methods as well as cell-based assays we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in various disease model systems. By analysing the protein sequences of these modifiers, we discovered a recurrent presence of coiled-coil domains in ataxin-1 toxicity enhancers, while such domains were not present in suppressors. This suggests that coiled-coil domains contribute to the aggregation- and toxicity-promoting effects of modifiers in mammalian cells. Our studies contribute to a deeper understanding of protein misfolding and aggregation in different NDs and highlight potential therapeutic targets for further investigations.