Alpha-synuclein oligomers: a new hope

Abstract

Alpha-synuclein is a protein implicated in Parkinson's disease and thought to be one of the main pathological drivers in the disease, although it remains unclear how this protein elicits its neurotoxic effects. Recent findings indicate that the assembly of toxic oligomeric species of alpha-synuclein may be one of the key processes for the pathology and spread of the disease. The absence of a sensitive in situ detection method has hindered the study of these oligomeric species and the role they play in the human brain until recently. In this review, we assess the evidence for the toxicity and prion-like activity of oligomeric forms of alpha-synuclein and discuss the advances in our understanding of the role of alpha-synuclein in Parkinson's disease that may be brought about by the specific and sensitive detection of distinct oligomeric species in post-mortem patient brain. Finally, we discuss current approaches being taken to therapeutically target alpha-synuclein oligomers and their implications.

Keywords: Aggregation; Alpha-synuclein; Detection-method; Oligomers; Parkinson’s.

Fig. 1

A-syn oligomers play a central role in the multi-factorial causes of Parkinson’s disease. A-syn oligomers, as well as other a-syn variants, actively participate in disrupting mitochondrial function, autophagy and lysosomal degradation, membrane homeostasis, ER function and synapses, and can induce inflammation. Mitochondrial defects/fragmentation have been observed after insult with a-syn oligomers. A-syn oligomers can also cause calcium accumulation and complex dysfunction inside the mitochondria. ER stress and dysfunction a-syn oligomers associate with ER membranes and cause ER stress. Proteasomal dysfunction while the proteasome normally degrades proteins, a-syn oligomers can cause proteasomal dysfunction, which in turn results in the accumulation of a-syn oligomers. Inflammatory response microglial cells respond to a-syn oligomers and produce neuro-inflammatory signals. Membrane damage oligomers can interact with the plasma membrane stabilizing previous damage and allowing the flow of calcium, which cause cellular distress. Autophagic/lysosomal block blocking the lysosomal and autophagic pathway results in oligomeric accumulation of a-syn and its detrimental effects. Synaptic dysfunction oligomers can bind to synaptobrevin, preventing SNARE complex formation and disrupting synaptic recycling of vesicles. They can also impair the interaction between kinsesin and microtubules, impairing vesicular transport, and finally, a dopaminergic catabolite has been shown to promote oligomerization of a-syn, leading to dopamine leak at the synapse

Fig. 2

Methods for the histological detection of a-syn oligomers/aggregates. a Schematic of the pathway of a-syn aggregation at the molecular level, from physiological monomers/tetramers, through oligomers and protofibrils to fibrils. b Different morphological species of a-syn found in Parkinson’s disease brain, which have been described following AS-IHC. Physiological/synaptic staining of a-syn is present in the neuropil and indicates the localization of physiological a-syn at synapses. Granular staining is interpreted as the presence of small aggregates. Lewy bodies are the pathological hallmark of Parkinson’s disease and consist of highly aggregated a-syn, while pale bodies consist of less compacted a-syn and are thought to be a precursor to Lewy bodies. Note that the exact relationship between the morphological and molecular species of a-syn is not clearly elucidated. c The species represented in a and b display differential resistance to proteinase K (PK), with structures on the right showing the highest PK resistance. d–h Represent techniques currently in use for the in situ detection of a-syn aggregates in human brain. Yellow bars correspond to the type of species detected by each technique in relation to a–c. d a-syn immunohistochemistry is the classical method for the detection of pathological a-syn (i.e. Lewy bodies), but staining of physiological a-syn is difficult to interpret. While a-syn oligomers may be detected, it is impossible to distinguish them from physiological staining. e A variety of oligomer specific antibodies that detect Lewy bodies have been developed using in vitro generated a-syn oligomers as immunogens. Images adapted from Kovacs et al. [77], with permission from the publisher. f The PK-PET blot requires a harsh treatment with PK, leading to the detection of small aggregates with high PK resistance and Lewy bodies. Images adapted from Schulz-Schaeffer [138], with permission from the publisher. g AS-PLA detects oligomers with intermediate proteinase K resistance which distribute diffusely in specific neuroanatomical areas and accumulate in early lesions such as Pale bodies. h The ideal technique(s) will specifically detect and differentiate multiple a-syn species to allow the role of each in the disease to be dissected

Fig. 3

Therapeutic avenues leading to oligomer burden decrease. Small molecules and immunization have the potential to inhibit a-syn intra- and extracellular interactions and, therefore, prevent aggregation, degrade existing aggregated complexes and avoid detrimental interactions with cellular components. Autophagic/lysosomal activation: small molecules that upregulate autophagy and/or lysosomal degradation will result in the reduction of a-syn oligomers and its beneficial effects. Proteasomal activation: as autophagic and lysosomal activation, proteasomal activation will result in an increased degradation of a-syn oligomers. Intracellular neutralization: small molecules capable to bind and/or breakdown will result in important intracellular consequences. However, anti-aggregating small molecules have the potential side-effect of causing a build-up of intermediate but toxic species, so careful toxicological evaluation of these compounds is warranted. Extracellular immunotherapy: immunotherapy will recruit glial cells in order to induce phagocytosis and neutralization of toxic oligomers. Reducing the oligomeric pool via extra- and intracellular therapeutic pathways will provide a significant downregulation of the pathological burden and, therefore, reduce the spread of a-syn toxic species