Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

Emin, Derya; Zhang, Yu P; Lobanova, Evgeniia; Miller, Aline F.; Li, Xuecong; Xia, Zengjie; Dakin, Helen; Sideris, Dimitrios I; Lam, Jeff; Ranasinghe, Rohan T.; Kouli, Antonina; Zhao, Yanyan; Dey, Arghya; Knowles, Tuomas P. J.; Vendruscolo, Michele; Ruggeri, Francesco Simone; Aigbirhio, Franklin I.; Williams‐Gray, Caroline H.; Klenerman, David

doi:10.1038/s41467-022-33252-6

Cited by 78 publications

(109 citation statements)

References 70 publications

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“…Results of a recent study by Emin et al [ 65 ] point to the most toxic types of synuclein aggregates. The authors developed a modification of α-synuclein aggregation reactions in the test tube with subsequent separation of aggregates by size.…”

Section: Synuclein-based Methods Of Disease Diagnosismentioning

confidence: 99%

“…Further experiments demonstrated that the soluble aggregates from PD patients’ brains were smaller and more inflammatory than the large aggregates in control brains. The authors conclude that the small non-fibrillar α-synuclein aggregates are the critical species causing neuroinflammation and disease progression [ 65 ].…”

Section: Synuclein-based Methods Of Disease Diagnosismentioning

confidence: 99%

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Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

Surguchov

Surguchev

2022

Biomedicines

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The synucleins are a family of natively unfolded (or intrinsically unstructured) proteins consisting of α-, β-, and γ-synuclein involved in neurodegenerative diseases and cancer. The current number of publications on synucleins has exceeded 16.000. They remain the subject of constant interest for over 35 years. Two reasons explain this unchanging attention: synuclein’s association with several severe human diseases and the lack of understanding of the functional roles under normal physiological conditions. We analyzed recent publications to look at the main trends and developments in synuclein research and discuss possible future directions. Traditional areas of peak research interest which still remain high among last year’s publications are comparative studies of structural features as well as functional research on of three members of the synuclein family. Another popular research topic in the area is a mechanism of α-synuclein accumulation, aggregation, and fibrillation. Exciting fast-growing area of recent research is α-synuclein and epigenetics. We do not present here a broad and comprehensive review of all directions of studies but summarize only the most significant recent findings relevant to these topics and outline potential future directions.

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Section: Synuclein-based Methods Of Disease Diagnosismentioning

confidence: 99%

Section: Synuclein-based Methods Of Disease Diagnosismentioning

confidence: 99%

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

Surguchov

Surguchev

2022

Biomedicines

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“…Furthermore, there can be a variety of types of aggregates, and whether and which aggregates are causing disease is still not fully clear. A recent study demonstrated that it is actually small soluble α-syn aggregates that cause toxicity to cells, and these resemble those found in the post-mortem patient’s brain [ 193 ]. A major question is also how a single protein is causing a spectrum of diseases.…”

Section: Conclusion and Futurementioning

confidence: 99%

Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study

et al. 2022

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Alpha-synuclein’s role in diseases termed “synucleinopathies”, including Parkinson’s disease, has been well-documented. However, after over 25 years of research, we still do not fully understand the alpha-synuclein protein and its role in disease. In vitro cellular models are some of the most powerful tools that researchers have at their disposal to understand protein function. Advantages include good control over experimental conditions, the possibility for high throughput, and fewer ethical issues when compared to animal models or the attainment of human samples. On the flip side, their major disadvantages are their questionable relevance and lack of a “whole-brain” environment when it comes to modeling human diseases, such as is the case of neurodegenerative disorders. Although now, with the advent of pluripotent stem cells and the ability to create minibrains in a dish, this is changing. With this review, we aim to wade through the recent alpha-synuclein literature to discuss how different cell culture setups (immortalized cell lines, primary neurons, human induced pluripotent stem cells (hiPSCs), blood–brain barrier models, and brain organoids) can help us understand aggregation pathology in Parkinson’s and other synucleinopathies.

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“…10 Prots et al demonstrated that αSyn oligomers disrupt axonal integrity in human neurons and that increased αSyn oligomerization by expressing oligomer-forming mutants (E46K and E57K) of αSyn resulted in impaired axonal transport of mitochondria. 11 Although most soluble oligomeric species of αSyn are toxic, 9 the molecular basis of toxicity remains to be established. 12 Therefore, the biophysical characterization of αSyn oligomers is essential for understanding their pathology and developing therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Determination of the Size and Shape of Single α-Synuclein Oligomers in Solution

Awasthi

Ying

et al. 2023

Preprint

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Soluble oligomers of amyloid-forming proteins are implicated as toxic species in the context of several neurodegenerative diseases. Since the size and shape of oligomers influences their toxicity, their biophysical characterization is essential for a better understanding of the structure-toxicity relationship. Amyloid oligomers are difficult to characterize by conventional approaches due to their heterogeneity in size and shape, their dynamic aggregation process, and their low abundance. This paper demonstrates that resistive-pulse measurements using polymer-coated solid-state nanopores enable label-free characterization of alpha Synuclein oligomers with single-particle resolution. This approach determines the size and shape of individual oligomers in solution and it interrogates hundreds of particles within minutes. A comparison of the resulting size distribution with single-particle analysis by transmission electron microscopy and mass photometry reveals good agreement and superior resolution. In addition, nanopore-based analysis is attractive due to its unique capability to combine rapid size analysis with an approximation of oligomer shape. Applying this shape approximation to putatively toxic oligomeric species that range in concentration from picomolar to nanomolar and in size from 11-25 mer (10S) and 19-39 mer (15S), revealed shapes that agree well with previous estimates by cryo-EM with the advantage that nanopore-based analysis occurs rapidly, in solution, and has the potential to become a widely accessible analysis technique.

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Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

Cited by 78 publications

References 70 publications

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study

Simultaneous Determination of the Size and Shape of Single α-Synuclein Oligomers in Solution

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