CHARACTERIZATION OF FUNCTIONAL HETEROMERIC AMYLOID FILAMENTS FORMED BY HUMAN NEUROPEPTIDES

Solid condensates formed by intrinsically disordered proteins (IDPs), such as amyloids, exhibit a highly organized and repetitive dynamic nature. Although traditionally associated with neurodegenerative diseases like Alzheimer’s and Parkinson’s, where they accumulate in aberrant forms, these aggregates also play essential native roles in physiological processes. One example is the intracellular storage and release strategy of neuropeptides via secretory granules in pituitary cells. Neuropeptides are signaling molecules produced and secreted by neurons, and they can act as neurotransmitters, neuromodulators, and hormones. Their great diversity enables the nervous system to regulate a wide variety of physiological and behavioral processes. These molecules are packaged within vesicles, concentrated, transported, and released — and during this process, they are stored in an amyloid-like form, as occurs with adrenocorticotropic hormone (ACTH). For this release to take place, the aggregation must be a reversible and tightly regulated process. However, the molecular mechanisms behind this aggregation and disaggregation remain unknown. This project focuses on the hormone ACTH, which is secreted in response to stress and is associated with the modulation of anxiety. Therefore, understanding these processes and their kinetics is potentially important for developing therapies against neurodegenerative diseases.