Alpha-Synuclein Aggregation Pathway in Parkinson's Disease: Current Status and Novel Therapeutic Approaches

Abstract

Following Alzheimer's, Parkinson's disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy is available. PD is tightly associated with α-synuclein (α-Syn) deposits, which become organised into insoluble, amyloid fibrils. As a typical intrinsically disordered protein, α-Syn adopts a monomeric, random coil conformation in an aqueous solution, while its interaction with lipid membranes drives the transition of the molecule part into an α-helical structure. The central unstructured region of α-Syn is involved in fibril formation by converting to well-defined, β-sheet rich secondary structures. Presently, most therapeutic strategies against PD are focused on designing small molecules, peptides, and peptidomimetics that can directly target α-Syn and its aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation of intracellular clearance with autophagy promoters, and degradation pathways based on immunotherapy of amyloid fibrils. In the present review, we sum marise the current advances related to α-Syn aggregation/neurotoxicity. These findings present a valuable arsenal for the further development of efficient, nontoxic, and non-invasive therapeutic protocols for disease-modifying therapy that tackles disease onset and progression in the future.

Keywords: disaggregators; high throughput anti-aggregation drug screening; intrinsically disordered proteins; protein misfolding; rationally designed peptidomimetics; structure/function relationship; synucleinopathies; α-synuclein oligomers and fibrils.

Figure 1

Structural diversity of α-Syn. Helical conformation of α-Syn bound to a membrane and intrinsically disordered α-Syn in solution are presented in the middle. Positively charged amino acid residues are given in blue, and negative ones in red. Secondary structure propensity was obtained by predictor FELLS [63]. Helical projections of N-terminal α-helices (a total of 60 amino acid residues and the first twenty) are generated using the HeliQuest web server [64]. The arrow shows the helical hydrophobic moment. The protein structure was predicted using AlfaFold2 [65]. The 3D protein structure was visualised in PyMOL v2 (available at: https://pymol.org/2/; accessed on 16 April 2022).

Figure 2

Three-dimensional models of α-Syn monomers (membrane-bound and unstructured in an aqueous solution) and oligomer (PDB ID: 2N0A; frontal and side view). Amino acid residues involved in the intermolecular interactions in oligomers, forming β-sheet rich core are shown in blue. N-terminal regions of monomers are denoted in blue, while C-termini are denoted in red. The monomer structures were predicted using AlfaFold2 [65]. The 3D protein structure was visualised in PyMOL v2 (available at: https://pymol.org/2/; accessed on 16 April 2022).

Figure 3

Five major developing α-Syn-targeting therapeutic strategies. They include reducing α-Syn transcription (1) and translation (2), inhibiting α-Syn aggregation by disaggregators involving low-molecular-weight compounds identified by high-throughput screening and rationally designed peptides or peptidomimetics (3), enhancing α-Syn clearance and degradation through autophagy and the ubiquitin-proteasome system (4), and capturing the toxic α-Syn forms in the extracellular space and blocking their transcellular spreading via immunotherapies (5).