Heterotypic interactions in amyloid diseases

Neurodegenerative disorders, such Alzheimer's, Amyotrophic Lateral Sclerosis and Parkinson's, affect nowadays an ever-growing number of people all over the world. These chronic and progressive diseases are responsible for devastating cognitive and motor impairments, which dramatically condition the life-quality of patients. Several effective treatments are continually in development, still the pathology and molecular mechanisms of these diseases remain largely unclear. The most evident pathological hallmark comment to these diseases is the presence of intra- and extra-cellular amyloid deposits. Amyloid are ordered protein aggregates, composed by unrelated proteins that have a propensity to self-assemble under disease related conditions. Recent observations suggest that misfolded proteins associated to different neurodegenerative disorders can synergize, often resulting in accelerated and severe disease progression. This project will start from the observation that amyloid aggregation is a specific assembly process that involves the formation of intermolecular beta-structures by short aggregation prone regions of the aggregating proteins. Although this is a self-assembly process, it also predicts co-aggregation is possible between proteins that share similar aggregation prone regions. Interestingly, such regions with high similarity have been identified in protein involved in neurodegenerative amyloid pathologies. A combination of bioinformatics, biophysics and cell culture will be used to study the co-aggregation and cross-seeding networks of representative disease associated aggregating proteins, first and foremost focusing on tau and beta, hallmarks of Alzheimer's disease.