α-synuclein-assisted oligomerization of β-amyloid (1–42)

Chau, Edward; Kim, Jin Ryoun

doi:10.1016/j.abb.2022.109120

Cited by 12 publications

(23 citation statements)

References 89 publications

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“…Although it has previously been reported that α-syn aggregation is triggered by Aβ42 (40) and that Aβ42 aggregation is inhibited by α-syn (37), our findings unify the mechanism of this co-aggregation which has previously remained elusive (Fig. 5).…”

Section: Discussionsupporting

confidence: 80%

“…Recently, it has been found that α-syn can either accelerate or inhibit the aggregation of Aβ. This dual mechanism of α-syn has been observed on both the 40-residue-long (Aβ40) and the 42-residue-long (Aβ42) isoforms of Aβ (22,(34)(35)(36)(37)(38). Whether α-syn promotes or inhibits Aβ aggregation seems to depend on the aggregated state of α-syn.…”

Section: Introductionmentioning

confidence: 95%

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α-Synuclein Aggregation is Triggered by Amyloid-β Oligomers via Heterogeneous Primary Nucleation

Vadukul

Thrush

Jin

et al. 2022

Preprint

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Neurodegenerative diseases are associated with the formation of amyloids in the nervous system. An increasing number of cases where amyloids of the same protein are found in different dementias is being reported. This observation complicates diagnosis and clinical intervention. Amyloids of the amyloid-β peptide or the protein α-synuclein are traditionally considered hallmarks of Alzheimer's and Parkinson's diseases, respectively. However, the co-occurrence of amyloids of these proteins has also been reported in patients diagnosed with either disease. Here, we provide new evidence about the protein composition of aggregates formed when these two proteins are co-present. We show that soluble species of amyloid-β can induce the aggregation of α-synuclein. The amyloid fibrils formed under these conditions are solely composed of α-synuclein to which amyloid-β can be found associated, but not as part of the core of the fibrils. Our data take us one step closer to understanding the complex nature of heterogenous aggregation in disease contexts which may aid clinical diagnosis and the development of therapeutic interventions.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 95%

α-Synuclein Aggregation is Triggered by Amyloid-β Oligomers via Heterogeneous Primary Nucleation

Vadukul

Thrush

Jin

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Regarding the variety of synucleinopathies, the RT-FAST is the first step in the development of ultrasensitive in vitro assays to indirectly detect amyloids in patients’ biological fluids as biomarkers based on nanopore technology. Besides that, the RT-FAST is also a promising tool for fundamental investigation of the protein aggregation process including the impact of cross-seeding, , coassembly, , or inhibitors, , leading future advances in the understanding of the lag phase of amyloidogenesis.…”

Section: Discussionmentioning

confidence: 99%

Real-Time Fast Amyloid Seeding and Translocation of α-Synuclein with a Nanopipette

et al. 2022

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The detection to α-synuclein (αS) assemblies as a biomarker of synucleinopathies is an important challenge for further development of an early diagnosis tool. Here, we present proof of concept real-time fast amyloid seeding and translocation (RT-FAST) based on a nanopipette that combines in one unique system a reaction vessel to accelerate the seed amplification and nanopore sensor for single-molecule αS assembly detection. RT-FAST allows the detection of the presence αS seeds WT and A53T variant in a given sample in only 90 min by adding a low quantity (35 μL at 100 nM) of recombinant αS for amplification. It also shows cross-seeding aggregation by adding mixing seeds A53T with WT monomers. Finally, we establish the dependence between the capture rate of aggregates by the nanopore sensor and the initial seed concentration from 200 pM to 2 pM, which promises further development toward a quantitative analysis of the initial seed concentration.

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“…Monomeric, oligomeric, and fibrillar (f-) Aβ can be incorporated into αS fibrils. Red arrows: specific to Aβ42-αS ( Chau and Kim, 2022 ). αS fibrils partially interferes with conversion of soluble Aβ42, but not Aβ40, into insoluble aggregates, instead possibly promoting the formation of large oligomeric Aβ42.…”

Section: Conformer-specific Aβ-αs Interactions: αS-assisted Oligomeri...mentioning

confidence: 99%

“…The subsequent study showed both similarities and dissimilarities between Aβ42-αS and Aβ40-αS interactions. Specifically, while monomeric and oligomeric αS promoted oligomerization of Aβ42, similar to Aβ40, αS fibrils induced the formation of large Aβ42 oligomers - a finding unique to Aβ42 ( Figure 2 ; Table 1 ) ( Chau and Kim, 2022 ). The C-terminus of Aβ42 is primarily utilized for its interactions with αS, similar to Aβ40, yet other regions of Aβ42 (e.g., Aβ22-35) are also involved ( Chau and Kim, 2022 ).…”

Section: Conformer-specific Aβ-αs Interactions: αS-assisted Oligomeri...mentioning

confidence: 99%

Oligomerization by co-assembly of β-amyloid and α-synuclein

Kim

2023

Front. Mol. Biosci.

Self Cite

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Aberrant self-assembly of an intrinsically disordered protein is a pathological hallmark of protein misfolding diseases, such as Alzheimer’s and Parkinson’s diseases (AD and PD, respectively). In AD, the 40–42 amino acid-long extracellular peptide, β-amyloid (Aβ), self-assembles into oligomers, which eventually aggregate into fibrils. A similar self-association of the 140 amino acid-long intracellular protein, α-synuclein (αS), is responsible for the onset of PD pathology. While Aβ and αS are primarily extracellular and intracellular polypeptides, respectively, there is evidence of their colocalization and pathological overlaps of AD and PD. This evidence has raised the likelihood of synergistic, toxic protein-protein interactions between Aβ and αS. This mini review summarizes the findings of studies on Aβ-αS interactions related to enhanced oligomerization via co-assembly, aiming to provide a better understanding of the complex biology behind AD and PD and common pathological mechanisms among the major neurodegenerative diseases.

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α-synuclein-assisted oligomerization of β-amyloid (1–42)

Cited by 12 publications

References 89 publications

α-Synuclein Aggregation is Triggered by Amyloid-β Oligomers via Heterogeneous Primary Nucleation

α-Synuclein Aggregation is Triggered by Amyloid-β Oligomers via Heterogeneous Primary Nucleation

Real-Time Fast Amyloid Seeding and Translocation of α-Synuclein with a Nanopipette

Oligomerization by co-assembly of β-amyloid and α-synuclein

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