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.

Antibodies against alpha‐synuclein: tools and therapies

“…), and that late stage Lewy bodies, composed primarily of α‐syn fibrils, may be less toxic (Caughey and Lansbury ; Bengoa‐Vergniory et al . ). Such a proposition is consistent with neuropathological studies reporting widespread Lewy body pathology without clinically significant motor or cognitive symptoms (Parkkinen et al .…”

“…During the lag phase, there is an accumulation of oligomers (soluble species without fibrillar conformation) which, over time, develop into fibrils (El-Agnaf et al 2003bPaleologou et al 2005Paleologou et al , 2009Tokuda et al 2010). There is converging evidence to indicate that intermediate oligomers or protofibrils are particularly cytotoxic (El-Agnaf et al 2003a;Winner et al 2011;Helwig et al 2016), and that late stage Lewy bodies, composed primarily of a-syn fibrils, may be less toxic (Caughey and Lansbury 2003;Bengoa-Vergniory et al 2017). Such a proposition is consistent with neuropathological studies reporting widespread Lewy body pathology without clinically significant motor or cognitive symptoms (Parkkinen et al 2005;Frigerio et al 2011) and the lack of relationship between severity of Lewy body deposition and important clinical variables such as disease duration or severity (Colosimo et al 2003;Parkkinen et al 2008).…”

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…The presence of α‐synuclein‐containing insoluble inclusions in neuronal soma or neurites, called Lewy bodies or Lewy neurites, respectively, is the major histopathological hallmark of PD (Spillantini, Crowther, Jakes, Hasegawa, & Goedert, ). Under normal conditions, α‐synuclein, an abundant protein located in presynaptic terminals, exists in monomeric, oligomeric, and aggregated forms in equilibrium (Bengoa‐Vergniory, Roberts, Wade‐Martins, & Alegre‐Abarrategui, ). However, under unknown pathological conditions, Lewy bodies and Lewy neurites are formed and spread spatially and temporally in a prion‐like fashion (Braak et al., ; Kordower, Chu, Hauser, Freeman, & Olanow, ; Li et al., ).…”

Seeding variability of different alpha synuclein strains in synucleinopathies

“…3 Given that DLB and PDD show overlapping clinical and pathological features, [4][5][6] it appears controversial whether they are different diseases or clinical manifestations of the same Lewy bodies disease spectrum. 9 Accumulating evidences [9][10][11][12] suggest that aggregates in synucleinopathies derive from α-synuclein misfolding and aggregation by contacting and converting its native counterpart into the misfolded one, behaving as a prion-like molecule. 9 Accumulating evidences [9][10][11][12] suggest that aggregates in synucleinopathies derive from α-synuclein misfolding and aggregation by contacting and converting its native counterpart into the misfolded one, behaving as a prion-like molecule.…”