Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding

By Karin M. Danzer, Dorothea Haasen, Anne R. Karow, Simon Moussaud, M. Habeck, A. Giese, H. Kretzschmar, B. Hengerer, Marcus Kostka. Journal of Neuroscience, 2007

680 citations recorded by the source corpus.

Aggregation of α-synuclein (α-syn) has been linked to the pathogenesis of Parkinson's disease (PD) and other neurodegenerative diseases. Increasing evidence suggests that prefibrillar oligomers and protofibrils, rather than mature fibrils of α-syn, are the pathogenic species in PD. Despite extensive effort on studying oligomerization of α-syn, no studies have compared different oligomer species directly on a single-particle level and investigated their biological effects on cells. In this study, we applied a novel highly sensitive single molecule detection system that allowed a direct comparison of different oligomer types. Furthermore, we studied biological effects of different oligomer types on cells. For this purpose, we developed new oligomerization protocols, that enabled the use of these different oligomers in cell culture. We found that all of our three aggregation protocols resulted in heterogeneous populations of oligomers. Some types of oligomers induced cell death via disruption of cellular ion homeostasis by a presumably pore-forming mechanism. Other oligomer types could directly enter the cell resulting in increased α-syn aggregation. Based on our results, we propose that under various physiological conditions, heterogeneous populations of oligomeric forms will coexist in an equilibrium. These different oligomer types lead directly or indirectly to cell damage. Our data indicate that inhibition of early α-syn aggregation events would consequently prevent all α-syn oligomer related toxicities. This has important implications for the development of disease-modifying drugs for the treatment of PD and other synucleinopathies.

Subfields: Neurology

View Paper: https://www.semanticscholar.org/paper/dc562af3384197eb7b3b5d34c8c71811255de6e9

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In Neurology

1. Vladimir N Uversky
2. Leonidas Stefanis
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Citations in the corpus

• Exosomal cell-to-cell transmission of alpha synuclein oligomers (2012, background): “Exosome-associated αsyn oligomers are more prone to internalization than exosome-free αsyn oligomers It has been reported that recombinant αsyn or αsyn oligomers can be internalized by cells and result in various cellular effects [18-20,33,67].”
• Prion-like transmission of protein aggregates in neurodegenerative diseases (2010, background): “Another study reports that GFP-tagged α-synuclein oligomers added to culture media can be internalized by primary cortical neurons engineered to express α-synuclein tagged with red fluorescent protei”
• Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats (2014, background): “However, it is not clear which machinery is involved in the transport of different α-synuclein forms, especially the aggregated ones (oligomers and fibrils), which likely contribute to pathology of PD [10, 34, 50].”
• α-Synuclein in Parkinson's disease. (2012, background): “Indeed, there is some evidence for this, albeit still somewhat fragmentary, implicating primarily a-synuclein oligomers, which could form pores on cellular membranes or alter the properties of voltage-gated receptors, leading to excess calcium influx (Volles and Lansbury 2002; Danzer et al. 2007; He”
• Mechanisms Underlying Inflammation in Neurodegeneration (2010, neutral): “Recent reports indicate that the accumulation of α-synuclein can result in the formation of intermediate state oligomers, which lead to neuronal cell death (Danzer et al., 2007).”
• Α-synuclein misfolding and Parkinson's disease. (2012, methodology): “Investigation of α-synuclein oligomer formation in the presence of iron and alcohols at the single particle level using single-molecule fluorescence techniques and AFM showed that both alcohols and Fe were effective inducers of α-synuclein oligomerization at micromolar concentrations [88, 255].”
• Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders (2010, background): “In relation to this, experimental studies have recently shown that aggregated α-synuclein may be transferred between neurons by endocytosis [26,27,30].”
• Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson's disease. (2018, background): “Soluble α-synuclein oligomers can disrupt membranes (van Rooijen et al., 2008; Volles et al., 2001) and cause cell death both in vitro (Danzer et al., 2007; Kayed et al., 2003) and in animal models (Karpinar et al., 2009; Winner et al., 2011).”