Insights into the molecular mechanism of amyloid filament formation: Segmental folding of α-synuclein on lipid membranes

Antonschmidt, Leif; Dervişoğlu, Rıza; Sant, Vrinda; Movellan, Kumar Tekwani; Mey, Ingo; Riedel, Dietmar; Steinem, Claudia; Becker, Stefan; Andreas, Loren B.; Griesinger, Christian

doi:10.1126/sciadv.abg2174

Cited by 46 publications

(61 citation statements)

References 67 publications

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“…A similar study involving the identification of the aggregation intermediates in the presence of phospholipid membrane revealed that prefibrillar species contain two loop regions with residues 57 to 61 and 71 to 80 [305]. These intermediates then rearrange to species, which are fibrillar in nature, with most of the NAC region and the N-terminus (residues 38-80) forming the part of final fibril conformation [305]. Studies have also been reported with aggregates of Aβ, PrP, and tau, where distinct biological properties emanate due to structural differences between the polymorphs [28,[306][307][308][309].…”

Section: Phase Separation and Nucleation: Molecular Basis Of Fibril Polymorphismmentioning

confidence: 90%

“…These polymorphs display not only structural differences but also exhibit different biological activities [252]. A similar study involving the identification of the aggregation intermediates in the presence of phospholipid membrane revealed that prefibrillar species contain two loop regions with residues 57 to 61 and 71 to 80 [305]. These intermediates then rearrange to species, which are fibrillar in nature, with most of the NAC region and the N-terminus (residues 38-80) forming the part of final fibril conformation [305].…”

Section: Phase Separation and Nucleation: Molecular Basis Of Fibril Polymorphismmentioning

confidence: 95%

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Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Mehra¹,

Gadhe²,

Bera³

et al. 2021

Biomolecules

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Abnormal accumulation of aggregated α-synuclein (α-Syn) is seen in a variety of neurodegenerative diseases, including Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), Parkinson’s disease dementia (PDD), and even subsets of Alzheimer’s disease (AD) showing Lewy-body-like pathology. These synucleinopathies exhibit differences in their clinical and pathological representations, reminiscent of prion disorders. Emerging evidence suggests that α-Syn self-assembles and polymerizes into conformationally diverse polymorphs in vitro and in vivo, similar to prions. These α-Syn polymorphs arising from the same precursor protein may exhibit strain-specific biochemical properties and the ability to induce distinct pathological phenotypes upon their inoculation in animal models. In this review, we discuss clinical and pathological variability in synucleinopathies and several aspects of α-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains. The current review sheds light on the recent advances in delineating the structure–pathogenic relationship of α-Syn and how diverse α-Syn molecular polymorphs contribute to the existing clinical heterogeneity in synucleinopathies.

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Section: Phase Separation and Nucleation: Molecular Basis Of Fibril Polymorphismmentioning

confidence: 90%

Section: Phase Separation and Nucleation: Molecular Basis Of Fibril Polymorphismmentioning

confidence: 95%

Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Mehra¹,

Gadhe²,

Bera³

et al. 2021

Biomolecules

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show abstract

“…In addition, a very recent structural study demonstrated that phospholipid vesicles consisting of POPC/POPA (1:1, lipid to protein ratio of 5:1) induced the formation of twisted WT α-synuclein filaments of 10 – 15 nm in thickness with a helical pitch of 90 – 120 nm. 29 These results indicate that the morphology of α-synuclein filaments derived by lipid vesicles may depend on the lipid composition, protein to lipid ratio, and the mutation that may modulate α- synuclein bindings 16, 30 . Further studies are, therefore, needed to investigate the effect of those factors on the filament structure.…”

Section: Discussionmentioning

confidence: 84%

Untwisted α-synuclein Filaments formed in the Presence of Lipid Vesicles

Dasari

Dillard

Hojjatian

et al. 2021

Preprint

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Accumulation of filamentous aggregates of α-synuclein is a pathological hallmark of several neurodegenerative diseases including Parkinson’s disease (PD). Interaction between α-synuclein and lipids has been shown to play a critical role in aggregation of α-synuclein. Most structural studies have, however, been focused on α-synuclein filaments formed in the absence of lipids. Here, we report structural investigation of α-synuclein filaments assembled under the quiescent conditions in the presence of anionic lipid vesicles using electron microscopy (EM) including cryo-EM. Our transmission electron microscopy (TEM) analyses reveal that α-synuclein forms curly protofilaments at an early stage of aggregation. The flexible protofilaments were then converted to long filaments after a longer incubation of 30 days. More detailed structural analyses using cryo-EM reveal that the long filaments adopt untwisted structures with different diameters, which have not been observed in previous α-synuclein filaments formed in vitro. The untwisted filaments are rather similar to straight filaments with no observable twist that are extracted from patients with dementia with Lewy bodies. Our structural studies highlight the conformational diversity of α-synuclein filaments, requiring additional structural investigation of not only more ex vivo α-synuclein filaments, but also in vitro α-synuclein filaments formed in the presence of diverse co-factors to better understand the molecular basis of diverse molecular conformations of α-synuclein filaments.

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“…The amyloid aggregation pathway of α-syn begins when the protein misfolds and starts clustering. The species formed at this initial stage are composed of a small number of molecules that normally retain the structure of the native protein, being either highly disordered [25] or α-helix-enriched [26,27] intermediates. Only relatively weak intermolecular interactions are involved within these early aggregates and thus, they are typically unstable.…”

Section: Synucleinopathies and α-Synuclein Amyloid Formationmentioning

confidence: 99%

Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase

Franco

Velasco-Carneros

Alvarez

et al. 2021

Cells

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Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies.

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Insights into the molecular mechanism of amyloid filament formation: Segmental folding of α-synuclein on lipid membranes

Cited by 46 publications

References 67 publications

Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Untwisted α-synuclein Filaments formed in the Presence of Lipid Vesicles

Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase

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