Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

Scheres, Sjors H. W.; Ryskeldi-Falcon, Benjamin; Goedert, Michel

doi:10.1038/s41586-023-06437-2

Cited by 58 publications

(46 citation statements)

References 140 publications

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“…The amyloid structure provides an atomic-level neuropathology description, and model systems duplicating the amyloid structure can deepen our understanding of the molecular mechanism of amyloid diseases, which is conducive to developing therapeutic measures. 70 These studies, combined with our results, deepen the understanding of different amyloid structures of a specific disease or different diseases with similar amyloid structures at the atomic level and provide more accurate therapeutic implications for different amyloid conformations.…”

Section: Resultssupporting

confidence: 56%

Molecular mechanisms involved in the destabilization of two types of R3–R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin

Tang,

Sun,

Wan

et al. 2024

Phys. Chem. Chem. Phys.

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Section: Resultssupporting

confidence: 56%

Molecular mechanisms involved in the destabilization of two types of R3–R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin

Tang,

Sun,

Wan

et al. 2024

Phys. Chem. Chem. Phys.

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“…The recent resolution revolution in cryoEM has significantly advanced our structural understanding of the fibrillar amyloid state. − In contrast, the structure of intermediate oligomeric species remains largely uncharted, hampering the development of oligomer-focused therapeutic strategies, despite their potential clinical relevance. For instance, lecanemab, an FDA-approved monoclonal antibody, mitigates cognitive decline in Alzheimer’s disease by binding soluble Aβ aggregates (oligomers and protofibrils) with high selectivity over monomers …”

Section: Discussionmentioning

confidence: 99%

A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion

Santos,

Cuellar,

Pallarès

et al. 2024

J. Am. Chem. Soc.

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Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36−61) that populates a distinct conformation in the mono-and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in αsynuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.

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“…kinetically isolated from other macrostates) that they are even heritable [122,[145][146][147][148][149][150][151]. Homo-and hetero-polymerisation and their catalysis are then referred to, respectively, as (self-)'seeding' [140,[152][153][154][155][156][157][158][159][160][161][162][163][164][165][166] and 'cross-seeding' [153,[167][168][169][170][171][172][173][174].…”

Section: (And Healthmentioning

confidence: 99%

Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

Grixti,

Theron,

Salcedo-Sora

et al. 2024

Preprint

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Nattokinase, from the Japanese fermented food natto, is a protease with fibrinolytic activity that can thus degrade conventional blood clots. In some cases, however, including in Long COVID, fibrinogen can polymerise into an anomalous amyloid form to create clots that are resistant to normal fibrinolysis and that we refer to as fibrinaloid microclots. These can be detected with the fluorogenic stain thioflavin T. We describe an automated microscopic technique for the quantification of fibrinaloid microclot formation, which also allows the kinetics of their formation and aggregation to be recorded. We also here show that recombinant nattokinase is effective at degrading the fibrinaloid microclotsin vitro. This adds to the otherwise largely anecdotal evidence, that we review, that nattokinase might be anticipated to have value as part of therapeutic treatments for individuals with Long COVID and related disorders that involve fibrinaloid microclots.

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Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

Cited by 58 publications

References 140 publications

Molecular mechanisms involved in the destabilization of two types of R3–R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin

Molecular mechanisms involved in the destabilization of two types of R3–R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin

A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion

Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease

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