Dynamics of α‐synuclein aggregation and inhibition of pore‐like oligomer development by β‐synuclein

Abstract

In recent years, new hope for understanding the pathogenesis of Parkinson's disease (PD) and Lewy body dementia (LBD) has emerged with the discovery of mutations and duplications in the a-synuclein (a-syn) gene that are associated with rare familial forms of Parkinsonism [1][2][3]. Moreover, it has been shown that a-syn is centrally involved in the pathogenesis of both sporadic and inherited forms of PD and LBD because this molecule accumulates in Lewy bodies (LBs) [4][5][6], synapses, and axons, and its expression in transgenic (tg) mice [7][8][9] and Drosophila [10] mimics several aspects of PD.The mechanisms through which a-syn leads to neurodegeneration and the characteristic symptoms of LBD are unclear. However, recent evidence indicates that abnormal accumulation of misfolded a-syn in the Accumulation of a-synuclein resulting in the formation of oligomers and protofibrils has been linked to Parkinson's disease and Lewy body dementia. In contrast, b-synuclein (b-syn), a close homologue, does not aggregate and reduces a-synuclein (a-syn)-related pathology. Although considerable information is available about the conformation of a-syn at the initial and end stages of fibrillation, less is known about the dynamic process of a-syn conversion to oligomers and how interactions with antiaggregation chaperones such as b-synuclein might occur. Molecular modeling and molecular dynamics simulations based on the micelle-derived structure of a-syn showed that a-syn homodimers can adopt nonpropagating (head-to-tail) and propagating (head-to-head) conformations. Propagating a-syn dimers on the membrane incorporate additional a-syn molecules, leading to the formation of pentamers and hexamers forming a ring-like structure. In contrast, b-syn dimers do not propagate and block the aggregation of a-syn into ring-like oligomers. Under in vitro cell-free conditions, a-syn aggregates formed ring-like structures that were disrupted by b-syn. Similarly, cells expressing a-syn displayed increased ion current activity consistent with the formation of Zn 2+ -sensitive nonselective cation channels. These results support the contention that in Parkinson's disease and Lewy body dementia, a-syn oligomers on the membrane might form pore-like structures, and that the beneficial effects of b-synuclein might be related to its ability to block the formation of pore-like structures.Abbreviations aa, amino acid; a-syn, a-synuclein; b-syn, b-synuclein; GFP, green fluorescent protein; LBD, Lewy body disease; PD, Parkinson's disease; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; tg, transgenic.

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

“…The final concentration of α-syn oligomers was determined by amino acid analysis. inhibitor of α-syn fibrillization 22 or by replacing monomeric α-syn by β-synuclein (β-syn), a close α-syn homolog that lacks the NAC (non-Aβ component) region, does not form fibrils 36 and inhibits α-syn fibrillization and inclusion formation in vitro 37 and in vivo, 38 respectively. Remarkably, the addition of Tolcapone significantly reduced α-syn mixture-induced toxicity in both M17 cells and primary neurons, indicating that fibrillar growth contributes to the toxic event (Figure 5a and Supplementary Figure S5A).…”

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

“…In this follow-up study, we identified putative multimers of two monomeric αSyn species of 14 and 17 kDa that included putative dimers (∼28 and 35 kDa), and tetramers (∼56 kDa) using a combination of biochemical techniques. The recognition of this pattern suggests the possible existence of two likely pathways for the aggregation of αSyn in vivo, a principle first suggested by molecular modeling of αSyn aggregates (36) and recently integrated into the proposed mechanisms of αSyn aggregation and propagation (3). This hypothesis is further supported by the existence of divergent detections of o-αSyn by the homotypic LB509 and heterotypic LB509-A11 pairs used for the ELISA studies, as recently reported for Aβ (37).…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…α-Syn was initially identified in AD brains associated with plaque formation and neurodegeneration [116,117]. The abnormal aggregation of α-syn is correlated with the neuropathological changes observed in PD and other synucleinopathies [13,118], and therefore inhibiting α-syn aggregation would be a key mechanism for preventing its toxicity.…”