WP4 aims to investigate the involvement of IDRs in diseases, with the ultimate goal of providing data and tools for diagnosis and therapeutics. IDRs play critical roles in protein Liquid-Liquid Phase Separation (LLPS) and protein self- assembly, processes that have been implicated in a range of diseases, including neurodegenerative disorders. Therefore, these regions represent promising therapeutic targets for mitigating abnormal LLPS and protein aggregation, with initial therapeutic interventions already emerging. However, to effectively target these proteins/regions, proper identification and classification are essential.
In many cases, the onset, penetrance, or clinical severity of diseases relies on mutations occurring within the IDRs of proteins associated with these pathologies. Even in the absence of mutations, the aggregation of a specific protein can lead to different diseases or variations in the manifestation of the same disorder. This phenomenon is exemplified in neurodegenerative diseases, where amyloid structural polymorphism plays a central role in pathogenesis, clinical manifestation, and the spread of pathology, presenting a significant challenge for therapeutic interventions. Another independent way in which IDRs contribute to disease is through their involvement in host-parasite interactions, particularly through structural mimicry.
In this scenario, parasite IDPs adopt features of host proteins to subvert cellular processes. Additionally, IDPs aid in evading immune surveillance and establishing infection.
WP4 focuses on exploring the involvement of IDRs in disease pathology. Another objective of WP4 is to analyze IDRs as determinants of amyloid structural polymorphism and clinical phenotypes in neurodegenerative disorders.