Multifaceted interactions mediated by intrinsically disordered regions play key roles in alpha synuclein aggregation

The aggregation of Alpha Synuclein (α-Syn) into fibrils is associated with the pathology of several neurodegenerative diseases. Pathologic aggregates of α-Syn adopt multiple fibril topologies and are known to be transferred between cells via templated seeding. Monomeric α-Syn is an intrinsically disordered protein (IDP) with amphiphilic N-terminal, hydrophobic-central, and negatively charged C-terminal domains. Here, we review recent work elucidating the mechanism of α-Syn aggregation and identify the key and multifaceted roles played by the N- and C-terminal domains in the initiation and growth of aggregates as well as in the templated seeding involved in cell-to-cell propagation. The charge content of the C-terminal domain, which is sensitive to environmental conditions like organelle pH, is a key regulator of intermolecular interactions involved in fibril growth and templated propagation. An appreciation of the complex and multifaceted roles played by the intrinsically disordered terminal domains suggests novel opportunities for the development of potent inhibitors against synucleinopathies.