Table 1. Exogenous factors affecting α-synuclein fibril formation in vitro.
| Factor | Description | References |
|---|---|---|
| Factors accelerating fibrillization | ||
| Agrochemicals | Pesticides (rotenone, dieldrin, paraquat) bound to the partially folded intermediate conformation of α-synuclein and induced its conformational changes to β-sheet enriched structures. | 85,89 |
| Polycations | α-synuclein bound to different polycations (spermine, polylysine, polyarginine, polyethyleneimine) forming stable complexes. Complex formation did not cause significant changes in α-synuclein secondary structures, as shown by far-UV CD spectroscopy. | 77 |
| Histones | Bovine histone H1 and bovine core histones (a mixture of H2a, H2b, H3 and H4) accelerated α-synuclein fibrillization in a dose-dependent manner. The formation of α-synuclein-histone complexes was not accompanied by significant changes in either secondary structure (CD) or globular structure (SAX). | 103 |
| Metal ions | Several divalent and trivalent ions (copper, iron, cobalt and manganese) accelerated α-synuclein fibrillization. Metal ions induced a conformational change of α-synuclein and led to the formation of a partially folded intermediate. | 76 |
| Glycosaminoglycans (GAGs) | Some glycosaminoglycans (heparin, heparin sulfate, agrin) and other highly sulfated polymers (dextran sulfate) significantly accelerated the formation of α-synuclein fibrils in vitro. Binding to α-synuclein induced conformational changes of the protein. | 87,157 |
| Sodium dodecyl sulfate | SDS stimulated α-synuclein fibrillization in a highly reproducible manner. SDS-induced fibrils did not exhibit the classical rod-like structure. Fibrillization in the presence of SDS seems to present an alternative fibrillization pathway. | 158 |
| Organic solvents | Organic solvents affected fibrillization kinetics in a concentration-dependent fashion. Low concentrations of alcohols accelerated the rate of fibrillization, whereas at high concentrations the effect was dependent on the type of alcohol—simple alcohols induced β-helix-rich conformation, fluorinated alcohols promoted α-helix-rich species. All solvents induced folding of α-synuclein, as shown by far-UV CD and FTIR spectra. | 73,111 |
| Factors inhibiting fibrillization | ||
|---|---|---|
| Small chemical compounds | Different chemical classes of compounds have been shown to inhibit α-synuclein fibrillization in vitro (polyphenols, benzothiazoles, phenothiazoles, steroids, Congo red and its derivatives, flavonoids). Some of them were able to disaggregate the preformed fibrils. | 44,104 |
| Heat shock proteins (Hsp) | Small Hsp proteins (αB-crystallin, HspB8, Hsp27, HspB2B3) inhibited α-synuclein fibrillization. The formation of aggregates suggested that Hsp proteins may redirect α-synuclein from a fibril-formation pathway toward an amorphous aggregation pathway. Hsp70 inhibited α-synuclein filament formation by binding to soluble prefibrillar intermediates. |
105-108 |
| PAMAM dendrimers | PAMAM dendrimers (generations G3, G4, and G5) inhibited fibrillization of α-synuclein and promoted the breakdown of pre-existing fibrils. They induced structural changes in α-synuclein and redirected the protein to an amorphous aggregation pathway. | 109 |
| β- and γ-synucleins | β- and γ-synucleins increased the lag time and dramatically reduced the elongation rate of α-synuclein. β- and γ-synucleins could be incorporated into oligomeric intermediates leading to their stabilization. | 159 |
| Catecholamines | Several catecholamines, including L-DOPA and dopamine, were able to inhibit α-synuclein fibrillization and to dissolve the preformed fibrils in vitro. | 160 |
| Phospholipids | Acidic phospholipids induced α-helical structure in α-synuclein, thus preventing the formation of fibrils. | 161 |
| Rifampicin | Rifampicin inhibited α-synuclein fibrillization and disaggregated existing fibrils by stabilizing monomeric and soluble oligomeric forms. | 162 |
| Trehalose | Trehalose, a disaccharide, inhibited α-synuclein fibrillization and stimulated the formation of large amorphous aggregates. | 163 |
| Oxidative modifications | Oxidation of α-synuclein methionines, N-terminal acetylation, and Tyr-nitration have been reported as protective factors against fibrillization. | 164-166 |