Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

Hardenberg, Maarten C.; Sinnige, Tessa; Casford, Sam; Dada, Samuel; Poudel, Chetan; Robinson, Elizabeth A.; Fuxreiter, Mónika; Kaminksi, Clemens; Kaminski-Schierle, Gabriele; Nollen, Ellen A. A.; Dobson, Christopher M.; Vendruscolo, Michele

doi:10.1093/jmcb/mjaa075

Cited by 87 publications

(122 citation statements)

References 72 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…In order to make further progress, in this work we investigated whether it is possible to leverage the recent finding that α-synuclein can undergo a liquid-liquid phase separation process resulting in the formation of dense liquid condensates [18][19][20] . Liquid-liquid phase separation has recently emerged as a general phenomenon associated with a wide variety of cellular functions [21][22][23][24] and closely linked with human disease 22,[25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

“…A liquid-liquid phase separation process has been reported for a wide range of proteins implicated neurodegenerative conditions, including tau, FUS and TDP-43 [28][29][30] . Since it has also been shown that protein aggregation can take place within liquid condensates (or droplets) 19,25,[30][31][32][33][34] , we asked whether it is possible to characterise at the microscopic level the droplet-induced aggregation mechanism of α-synuclein.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Spontaneous nucleation and fast aggregate-dependent proliferation of α-synuclein aggregates within liquid condensates at physiological pH

Dada

Hardenberg

Mrugalla

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

It is well-established that ⍺-synuclein aggregation may proceed through an initial lipid-dependent aggregate formation and, if at acidic pH, a subsequent aggregate-dependent proliferation. It has also been recently reported that the aggregation of ⍺-synuclein may also take place through an alternative pathway, which takes place within dense liquid condensates produced through liquid-liquid phase separation. The microscopic mechanism of this process, however, remains to be clarified. Here, we developed a fluorescence-based assay to perform a kinetic analysis of the aggregation process of ⍺-synuclein within liquid condensates, and applied it to determine the corresponding mechanism of aggregation. Our analysis shows that at pH 7.4 the aggregation process of ⍺-synuclein within dense condensates starts with spontaneous primary nucleation followed by rapid aggregate-dependent proliferation. Taken together, these results reveal a highly efficient pathway for the appearance and proliferation of ⍺-synuclein aggregates at physiological pH.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spontaneous nucleation and fast aggregate-dependent proliferation of α-synuclein aggregates within liquid condensates at physiological pH

Dada

Hardenberg

Mrugalla

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Factors known to promote αSyn aggregation, such as low pH, phosphomimetic substitution and familial Parkinson's disease mutations, also promote αSyn LLPS and its subsequent maturation (Ray et al, 2020). It has also been reported that the maturation process towards the amyloid state is delayed in the presence of vesicles in vitro (Hardenberg et al, 2021). Therefore, the intermolecular interaction with the SDS micelle and folding of αSyn should be related to the suppression of the maturation process.…”

Section: Studies On Non-photoreactive Proteins Combining the Tg Methods With A Stopped Flow Apparatusmentioning

confidence: 99%

“…Therefore, the intermolecular interaction with the SDS micelle and folding of αSyn should be related to the suppression of the maturation process. Since LLPS of αSyn can be easily promoted by an addition of polyethylene glycol (PEG)-8000 ( Ray et al, 2020 ; Hardenberg et al, 2021 ), it would be interesting to detect the conformational change and assembly process for LLPS by the SF-TG method. By monitoring this reaction in the presence of vesicles or SDS-micelles, the suppression mechanisms of LLPS will be possibly clarified based on the kinetic information.…”

Section: Studies On Non-photoreactive Proteinsmentioning

confidence: 99%

A Time-Resolved Diffusion Technique for Detection of the Conformational Changes and Molecular Assembly/Disassembly Processes of Biomolecules

Nakasone

Terazima

2021

Front. Genet.

View full text Add to dashboard Cite

Biological liquid–liquid phase separation (LLPS) is driven by dynamic and multivalent interactions, which involves conformational changes and intermolecular assembly/disassembly processes of various biomolecules. To understand the molecular mechanisms of LLPS, kinetic measurements of the intra- and intermolecular reactions are essential. In this review, a time-resolved diffusion technique which has a potential to detect molecular events associated with LLPS is presented. This technique can detect changes in protein conformation and intermolecular interaction (oligomer formation, protein-DNA interaction, and protein-lipid interaction) in time domain, which are difficult to obtain by other methods. After the principle and methods for signal analyses are described in detail, studies on photoreactive molecules (intermolecular interaction between light sensor proteins and its target DNA) and a non-photoreactive molecule (binding and folding reaction of α-synuclein upon mixing with SDS micelle) are presented as typical examples of applications of this unique technique.

show abstract

“…In a recent study, Hardenberg and coauthors [40] described how the C. elegans model of PD helped to understand the relationship between α-synuclein self-assembly and the Lewy body formation. The authors tested a hypothesis that α-synuclein might be capable of irreversibly capturing cellular components through liquid-liquid phase separation.…”

Section: α-Synuclein Self-assembly and Lewy Body Formationmentioning

confidence: 99%

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Surguchov

2021

Cells

View full text Add to dashboard Cite

Parkinson’s disease (PD) is the second most common neurodegenerative disease, afflicting ~10 million people worldwide. Although several genes linked to PD are currently identified, PD remains primarily an idiopathic disorder. Neuronal protein α-synuclein is a major player in disease progression of both genetic and idiopathic forms of PD. However, it cannot alone explain underlying pathological processes. Recent studies demonstrate that many other risk factors can accelerate or further worsen brain dysfunction in PD patients. Several PD models, including non-mammalian eukaryotic organisms, have been developed to identify and characterize these factors. This review discusses recent findings in three PD model organisms, i.e., yeast, Drosophila, and Caenorhabditis elegans, that opened new mechanisms and identified novel contributors to this disorder. These non-mammalian models share many conserved molecular pathways and cellular processes with humans. New players affecting PD pathogenesis include previously unknown genes/proteins, novel signaling pathways, and low molecular weight substances. These findings might respond to the urgent need to discover novel drug targets for PD treatment and new biomarkers for early diagnostics of this disease. Since the study of neurodegeneration using simple eukaryotic organisms brought a huge amount of information, we include only the most recent or the most important relevant data.

show abstract

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

Cited by 87 publications

References 72 publications

Spontaneous nucleation and fast aggregate-dependent proliferation of α-synuclein aggregates within liquid condensates at physiological pH

Spontaneous nucleation and fast aggregate-dependent proliferation of α-synuclein aggregates within liquid condensates at physiological pH

A Time-Resolved Diffusion Technique for Detection of the Conformational Changes and Molecular Assembly/Disassembly Processes of Biomolecules

Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Contact Info

Product

Resources

About