Cryo-EM structure of alpha-synuclein fibrils amplified by PMCA from PD and MSA patient brains

Burger, Domenic; Fenyi, Alexis; Bousset, Luc; Stahlberg, Henning; Melki, Ronald

doi:10.1101/2021.07.08.451588

Cited by 32 publications

(42 citation statements)

References 85 publications

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“…Meanwhile, we notice two structural studies of α-syn fibrils amplified from PD brain homogenates post on BioRxiv recently. 13,28 Interestingly, in one study, the reported α-syn fibril structures are very similar to our Type 1a and 1b fibrils. 28 While, in the other study that applied four short cycles rather than one long cycle of amplification, the reported fibril structures are distinctive from any known wild-type α-syn fibril structures but similar to that formed by Y39-phosphorylated α-syn 13,29 , which may reflect the existence of pY39-like fibril conformation in the PD brain.…”

Section: Discussionsupporting

confidence: 85%

“…13,28 Interestingly, in one study, the reported α-syn fibril structures are very similar to our Type 1a and 1b fibrils. 28 While, in the other study that applied four short cycles rather than one long cycle of amplification, the reported fibril structures are distinctive from any known wild-type α-syn fibril structures but similar to that formed by Y39-phosphorylated α-syn 13,29 , which may reflect the existence of pY39-like fibril conformation in the PD brain. Taken together, the amplified fibrils from patients biological fluid and tissue samples may partially represent their mother fibrils.…”

Section: Discussionsupporting

confidence: 85%

“…Consistently, structural studies have shown that α-syn can form polymorphic fibril structures. 8-13 These findings suggest that distinct α-syn strains may cause the clinical and pathological heterogeneities of α-synucleinopathies.…”

Section: Introductionmentioning

confidence: 93%

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Different structures and pathologies of α-synuclein fibrils derived from preclinical and postmortem patients of Parkinson’s disease

Fan

Sun

et al. 2021

Preprint

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Abstractα-Synuclein (α-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinson’s disease (PD). Studies have shown that α-syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro α-syn aggregation, and the amplified fibrils are more potent in inducing endogenous α-syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of α-syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD α-syn aggregation and suggests potential alteration of α-syn fibrils during the progression of PD clinical phases.Significance StatementIncreasing evidence support different conformational α-syn fibrils in patients with different α-synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is unknown. Here, we show that α-syn fibrils amplified from the cerebrospinal fluid (CSF) of the late-stage postmortem PD (post-PD) patient are more potent in inducing endogenous α-syn aggregation in neurons than that amplified from the preclinical (pre-PD) patient. Cryo-EM structures further reveal that the post-PD fibrils contain a novel conformation that is distinct from either the pre-PD fibrils or those previously reported. Our work suggests conformational evolution of α-syn fibrils along with PD progression.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 85%

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Different structures and pathologies of α-synuclein fibrils derived from preclinical and postmortem patients of Parkinson’s disease

Fan

Sun

et al. 2021

Preprint

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“…Therefore, structural verification of seeds and seeded aggregates is required. For α-synuclein and immunoglobulin lightchain, cryo-EM has shown that using similar amplification methods, the structures of seeded filaments differed from those of the seeds under the conditions used (Burger et al, 2021;Lövestam et al, 2021;Radamaker et al, 2021). Full-length human tau is highly soluble, but truncated proteins encompassing the repeat region readily assemble into filaments that resemble AD PHFs by negative staining.…”

Section: Introductionmentioning

confidence: 99%

Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

Lövestam

Koh

Knippenberg

et al. 2022

eLife

179

166

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Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.

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“…However, they may not always amplify the predominant filamentous assemblies Therefore, structural verification of seeds and seeded aggregates is required. For α-synuclein and immunoglobulin light-chain, cryo-EM has shown that using similar amplification methods, the structures of seeded filaments were not the same as those of the seeds (Burger et al, 2021;Lövestam et al, 2021;Radamaker et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

Lövestam

Koh

Knippenberg

et al. 2021

Preprint

View full text Add to dashboard Cite

Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.

show abstract

Cryo-EM structure of alpha-synuclein fibrils amplified by PMCA from PD and MSA patient brains

Cited by 32 publications

References 85 publications

Different structures and pathologies of α-synuclein fibrils derived from preclinical and postmortem patients of Parkinson’s disease

Different structures and pathologies of α-synuclein fibrils derived from preclinical and postmortem patients of Parkinson’s disease

Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

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