Soluble endogenous oligomeric α-synuclein species in neurodegenerative diseases: Expression, spreading, and cross-talk

Abstract

There is growing recognition in the field of neurodegenerative diseases that mixed proteinopathies are occurring at greater frequency than originally thought. This is particularly true for three amyloid proteins defining most of these neurological disorders, amyloid-beta (Aβ), tau, and alpha-synuclein (αSyn). The co-existence and often co-localization of aggregated forms of these proteins has led to the emergence of concepts positing molecular interactions and cross-seeding between Aβ, tau, and αSyn aggregates. Amongst this trio, αSyn has received particular attention in this context during recent years due to its ability to modulate Aβ and tau aggregation in vivo, to interact at a molecular level with Aβ and tau in vivo and to cross-seed tau in mice. Here we provide a comprehensive, critical, and accessible review about the expression, role and nature of endogenous soluble αSyn oligomers because of recent developments in the understanding of αSyn multimerization, misfolding, aggregation, cross-talk, spreading and cross-seeding in neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, and Huntington's disease. We will also discuss our current understanding about the relative toxicity of endogenous αSyn oligomers in vivo and in vitro, and introduce potential opportunities to counter their deleterious effects.

Keywords: Amyloid-β; aggregation; cross-seeding; cross-talk; multimer; neurodegenerative disease; oligomer; tau; α-synuclein.

Fig. 1

Proposed model of αSyn assemblies in health (‘multimers’) and disease (‘oligomers’). Schematic of one cell and extracellular space. Under physiological conditions (in blue, bottom left), αSyn comes off the ribosome as a soluble unfolded monomer (blue ‘αSyn’), which forms helical monomers (blue circle) upon getting in contact with vesicle membranes. Helical monomers at membranes may assemble into metastable physiological multimers (low-n assemblies in blue) that eventually fall apart again, initiating a new cycle. Under stress of pathological conditions (in pink shading, starting bottom middle), excess of unfolded or helical membrane-bound αSyn has been proposed to be the starting point for pathological aggregation into oligomers including dimers, tetramers, annular protofibrils and larger oligomers. We propose that two distinct misfolded states of αSyn lead to two distinct aggregation pathways, one forming amyloid fibrils (ON pathway; A11^–/OC⁺), and one forming large non-fibrillar αSyn oligomers (OFF pathway, A11+/OC^–). Endogenous oligomeric αSyn are likely to be enriched for β-sheet motifs. The endpoint of intracellular aggregation is the so-called Lewy body (top left). Mixed intracellular aggregates have also been reported in particular with tau (red baton), although the exact αSyn oligomer interacting with tau is unknown (indicated by ‘?’). Cross-talks between αSyn species and huntingtin oligomers (Htt, orange hexagons) have also been advanced but require confirmation. Oligomers of αSyn may be released into the extracellular space by an ill-defined mechanism (right). There, they may further aggregate, which may include the formation of mixed aggregates, with amyloid-β peptides (Aβ, purple stars) in particular with which αSyn can form hybrid αSyn/Aβ oligomers. Extracellular aggregates may be taken up by cells and released into the cytosol where they may in turn ‘seed’ αSyn aggregation. Release, uptake and seeding of intracellular pathology might be underlying the phenomenon of αSyn spread and release might correspond to a possible protective mechanism adopted by cells to maintain cellular proteostasis.

Fig. 2

Relationships between 28-, 35- and 55 kDa αSyn oligomers in human brain tissue from cognitively intact subjects and subjects with AD within the ROS cohort. Regression analyses and quantile density contours for pair-wise comparisons between 35 kDa (A) or 28 kDa (B) dimeric αSyn and the ∼55–56 kDa putative αSyn tetramer detected in the intracellular-enriched fraction (IC). All species were detected with the monoclonal antibody 4D6. NCI, no cognitive impairment; AD, Alzheimer’s disease; ROS, Religious Orders Study.