More than 50 human diseases, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, involve the deposition of fibrillar protein aggregates [1]. α-Syn is an IDP that is found in the brain, particularly in the presynaptic nerve termini. Due to its intrinsically disordered nature, α-Syn has multivalent, weak, and reversible interactions that allow it to participate in both functional and misfolding pathways [2]. α-Syn has been associated with various synucleinopathies including Parkinson's disease (PD), dementia with Lewy body (DLB), and multiple system atrophy (MSA).

In disease, α-Syn can self-associate into multiple conformations including dimers and oligomers. These aggregates can go on to form amyloid fibrils that are incorporated into the Lewy bodies of patients with PD (Figure 1a) [3∗∗, 4, 5]. Additional disease progression is associated with a prion-like process of cell-to-cell transfer where fibril seeds are released from one neuron and taken up by a neighboring neuron [6, 7, 8]. This cellular uptake allows for endogenous α-Syn to interact with the fibril seed through elongation or secondary nucleation leading to further fibril growth (Figure 1b) [7,8]. It has been observed that α-Syn fibrils isolated from patients with different synucleinopathies are structurally distinct from each other [9]. These polymorphs also differ in their biological and pathological activity including seeding and cell-to-cell transfer.

α-Syn is frequently described as having three different domains: an amphiphilic N-terminal domain from residues 1–60 that contains imperfect KTKXGV repeats, a hydrophobic NAC domain from residues 61–95, and a negatively charged C-terminal domain from residues 96–140 [6]. α-Syn fibrils are characterized by the presence of parallel, in-register β-sheets, a common structural feature of amyloid fibrils. These fibril structures are stabilized via hydrogen bonding and “zippered” hydrophobic interactions formed by residues in the NAC domain [10].

In this review we discuss recent insights into the key and multifaceted roles played by the N- and C-terminal domains at all stages in the fibril aggregation process. We identify diverse intermolecular protein–protein interactions involving these domains that control early events in the aggregation process. Combining key results from recent studies, we propose that environment-dependent charge–charge interactions between monomer N- and fibril C-terminal domains are critical for fibril seeding and elongation. A molecular understanding of the intermolecular protein–protein interactions that arise during the fibril formation process provides a foundation for developing therapeutic strategies against aggregation in synucleinopathies.