Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Abstract

Misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell-to-cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that precede Lewy body formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. In the present study, we characterize, by ESI-ion mobility spectrometry (IMS)-MS, a specific population of α-syn oligomers. These MS-compatible oligomers were compared with oligomers with known seeding and pore-forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain-of-function. Structurally, the MS compatible oligomers populated a range of species from dimers through to hexamers. Lower-order oligomers were structurally diverse and consistent with unstructured assemblies. Higher-order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases.

Structural, morphological, and functional diversity of amyloid oligomers

“…In fact, there is some evidence that, in addition to that of fibrils, self-propagation of Ab [119,120] and tau [120][121][122] amyloid oligomers plays an important role in neurodegenerative diseases. Ab oligomers propagated faster than fibrils [28], and oligomer seeding has been shown for tau [121,123], a-synuclein [49,124], and ataxin [125]. Seeding was not completely sequence-specific, as cross-seeding was observed between oligomers of Ab and tau [123], Ab 40 and Ab 42 [126], TDP-43 and Ab [127], and human and rat IAPP [128].…”

The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

“…In addition, PD-causing α -synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation [51]. Extracellular oligomeric species that are also transmissible through exosomal vesicles [178] are highly abundant in the PD brain [115] and can promote α -synuclein aggregation in recipient cells [179]. Transmitted electron microscopy studies in the postmortem human brain of subjects affected by synucleinopathies, reporting the presence of oligomeric α -synuclein within the early-endosomal compartment of neuronal cells, are also in line with the idea that oligomers might be the transmissible species [13].…”

Looking at the recent advances in understanding α-synuclein and its aggregation through the proteoform prism

“…A crucial role of high-affinity binding of preformed α-synuclein fibrils to the lymphocyte-activation gene 3 protein is for the initiation of endocytosis and transmission of aggregated α-synuclein, thereby propagating its toxicity and leading to the loss of dopamine neurons and the development of biochemical and behavioral deficits in vivo 198 . Importantly, it is not only exogenous fibrillar forms of α-synuclein that are able to promote cellular pathologies, since soluble amyloid oligomers that precede LB formation were also linked to the cell-to-cell transmission of α-synuclein pathology 199 .…”