Glycosaminoglycans have variable effects on α-synuclein aggregation and differentially affect the activities of the resulting amyloid fibrils

Abstract

Parkinson's disease is mainly a sporadic disorder in which both environmental and cellular factors play a major role in the initiation of this disease. Glycosaminoglycans (GAG) are integral components of the extracellular matrix and are known to influence amyloid aggregation of several proteins, including α-synuclein (α-Syn). However, the mechanism by which different GAGs and related biological polymers influence protein aggregation and the structure and intercellular spread of these aggregates remains elusive. In this study, we used three different GAGs and related charged polymers to establish their role in α-Syn aggregation and associated biological activities of these aggregates. Heparin, a representative GAG, affected α-Syn aggregation in a concentration-dependent manner, whereas biphasic α-Syn aggregation kinetics was observed in the presence of chondroitin sulfate B. Of note, as indicated by 2D NMR analysis, different GAGs uniquely modulated α-Syn aggregation because of the diversity of their interactions with soluble α-Syn. Moreover, subtle differences in the GAG backbone structure and charge density significantly altered the properties of the resulting amyloid fibrils. Each GAG/polymer facilitated the formation of morphologically and structurally distinct α-Syn amyloids, which not only displayed variable levels of cytotoxicity but also exhibited an altered ability to internalize into cells. Our study supports the role of GAGs as key modulators in α-Syn amyloid formation, and their distinct activities may regulate amyloidogenesis depending on the type of GAG being up- or down-regulated .

Transcriptomic analysis of α-synuclein knockdown after T3 spinal cord injury in rats

“…The most famous role of scar tissue hinders the growth of axons [41]. Extracellular matrix components may affect the aggregation of α-Syn [42]. This study suggests that α-Syn silencing may alter the extracellular matrix, and that changes may affect the prognosis of SCI [43].…”

The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin

“…Despite the low affinity for heparin for full-length aSN, recent work has shown that GAGs such as heparin induce the fibrillation of full-length aSN at specific molar ratios and that the interactions are mainly with the N-terminal of aSN [ 28 , 29 ]. It is also known that heparin can induce the fibrillation of, for example, Tau [ 66 ], a protein involved in Alzheimer’s disease; transthyretin [ 67 ]; and non-amyloidogenic proteins [ 68 ], with different hypotheses for the heparin’s mode of action, one of which is as a scaffold for fibril formation, supporting fibril core structures.…”

“…The cationic (C) and polar (P) CPC clip motif is another heparin-binding motif, where two cationic residues separated by a polar residue facilitate heparin binding [ 27 ]. It has been reported that heparin influences the fibrillation of aSN in a concentration-dependent manner either through ionic interaction with the N-terminal [ 28 , 29 ] or via the stabilization of a transition state favoring the β-sheet structure [ 29 , 30 ]. Furthermore, heparin has been found integrated in fibrils [ 29 ].…”

“…Furthermore, heparin has been found integrated in fibrils [ 29 ]. Although the structural details are not known, heparin-induced fibrils of aSN have a different morphology to aSN fibrillated without heparin [ 28 , 31 ]. In addition, heparin may induce the fibrillation of proteins that are not inherently found to fibrillate [ 32 , 33 ].…”

Alpha-Synuclein Amyloid Aggregation Is Inhibited by Sulfated Aromatic Polymers and Pyridinium Polycation

“…As for alpha-synuclein, some sulfated polysaccharides stimulated its fibrillation (heparin, heparin sulfate, etc. ), but some of them did not (for example, keratan sulfate) [43,44]. Thus, there is extensive, but controversial and unsystematic information about the influence of biopolymers on the amyloid transformation of amyloidogenic proteins and, especially, little information about alpha-synuclein transformation.…”