The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges DOI Open Access

Huiting Zheng,

Huimin Sun, Qixu Cai

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(9), С. 4969 - 4969

Опубликована: Май 2, 2024

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer's disease over twenty neurodegenerative disorders. However, the molecular mechanisms tau in vivo remain incompletely understood. There two types aggregates brain: soluble (oligomers protofibrils) insoluble filaments (fibrils). Compared to filamentous aggregates, more toxic exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, its native state, is a highly soluble, heat-stable that does not form fibrils by itself, even when hyperphosphorylated. In vitro studies have found negatively charged molecules such as heparin, RNA, or arachidonic acid generally required induce aggregation. Two recent breakthroughs provided new insights into mechanisms. First, an intrinsically disordered protein, undergo liquid-liquid phase separation (LLPS) both inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar conformations associated with different Nonetheless, only core structurally resolved, remainder appears "fuzzy coat". From this review, it further (1) clarify role LLPS aggregation; (2) unveil structural features aggregates; (3) understand involvement fuzzy coat regions oligomer fibril formation.

Язык: Английский

Structures of α-synuclein filaments from human brains with Lewy pathology DOI
Yang Yang, Yang Shi, Manuel Schweighauser

и другие.

Nature, Год журнала: 2022, Номер 610(7933), С. 791 - 795

Опубликована: Сен. 15, 2022

Язык: Английский

Процитировано

270
Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids DOI
Sjors H. W. Scheres, Benjamin Falcon, Michel Goedert

и другие.

Nature, Год журнала: 2023, Номер 621(7980), С. 701 - 710

Опубликована: Сен. 27, 2023

Язык: Английский

Процитировано

110
Mechanisms and pathology of protein misfolding and aggregation DOI
Nikolaos Louros, Joost Schymkowitz, Frédéric Rousseau

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 24(12), С. 912 - 933

Опубликована: Сен. 8, 2023

Язык: Английский

Процитировано

105
Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases DOI
Dan Li, Cong Liu

Nature reviews. Neuroscience, Год журнала: 2022, Номер 23(9), С. 523 - 534

Опубликована: Май 30, 2022

Язык: Английский

Процитировано

75
Disease-specific tau filaments assemble via polymorphic intermediates DOI Creative Commons
Sofia Lövestam, David Li,

Jane L. Wagstaff

и другие.

Nature, Год журнала: 2023, Номер 625(7993), С. 119 - 125

Опубликована: Ноя. 29, 2023

Abstract Intermediate species in the assembly of amyloid filaments are believed to play a central role neurodegenerative diseases and may constitute important targets for therapeutic intervention 1,2 . However, structural information about intermediate has been scarce molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy study vitro recombinant truncated tau (amino acid residues 297–391) into paired helical Alzheimer’s disease or chronic traumatic encephalopathy 3 We report formation shared first filament, with an ordered core comprising 302–316. Nuclear magnetic resonance indicates that same adopt rigid, β-strand-like conformations monomeric tau. At later time points, disappears observe many different filaments, structures depend on reaction conditions. end both reactions, most disappear cores as those from human brains remain. Our results provide insights processes primary secondary nucleation assembly, implications design new therapies.

Язык: Английский

Процитировано

74
New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy DOI Creative Commons
Yang Yang, Holly J. Garringer, Yang Shi

и другие.

Acta Neuropathologica, Год журнала: 2023, Номер 145(5), С. 561 - 572

Опубликована: Фев. 27, 2023

Abstract A 21-nucleotide duplication in one allele of SNCA was identified a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion MAAAEKT after residue 22 α-synuclein, resulting protein 147 amino acids. Both wild-type and mutant proteins were present sarkosyl-insoluble material extracted from frontal cortex individual JOS examined by electron cryo-microscopy. The structures filaments, comprising either single protofilament, or pair protofilaments, revealed new fold differs folds Lewy body diseases multiple system atrophy (MSA). consists compact core, sequence which (residues 36–100 α-synuclein) is unaffected mutation, two disconnected density islands (A B) mixed sequences. There non-proteinaceous cofactor bound between core island A. resembles common substructure MSA Type I II dimeric its segment approximating C-terminal protofilaments B mimicking N-terminal arm partial similarity extends to locations their cofactor-binding sites. In vitro assembly recombinant mixture yielded distinct those filaments. Our findings provide insight possible mechanism fibrillation acids forms nucleus fold, around assemble during elongation.

Язык: Английский

Процитировано

45
Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases DOI Creative Commons
Dillon J. Rinauro, Fabrizio Chiti, Michele Vendruscolo

и другие.

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Фев. 20, 2024

The conversion of native peptides and proteins into amyloid aggregates is a hallmark over 50 human disorders, including Alzheimer's Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the formation process as primary cytotoxic agents in many these devastating conditions. In this review, we analyze processes by which are formed, their structures, physicochemical properties, population dynamics, mechanisms cytotoxicity. We then focus on drug discovery strategies that target ability to disrupt cell physiology trigger degenerative processes.

Язык: Английский

Процитировано

43
Molecular Crowding: The History and Development of a Scientific Paradigm DOI Creative Commons
Caterina Alfano, Yann Fichou, Klaus Huber

и другие.

Chemical Reviews, Год журнала: 2024, Номер 124(6), С. 3186 - 3219

Опубликована: Март 11, 2024

It is now generally accepted that macromolecules do not act in isolation but "live" a crowded environment, is, an environment populated by numerous different molecules. The field of molecular crowding has its origins the far 80s became only end 90s. In present issue, we discuss various aspects are influenced and need to consider effects. This Review meant as introduction theme analysis evolution concept through time from colloidal polymer physics more biological perspective. We introduce themes will be thoroughly treated other Reviews issue. our intentions, each may stand itself, complete collection aspiration provide complementary perspectives propose holistic view crowding.

Язык: Английский

Процитировано

37
Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C DOI Creative Commons
Diana Arseni, Takashi Nonaka, Max Jacobsen

и другие.

Nature, Год журнала: 2024, Номер 634(8034), С. 662 - 668

Опубликована: Сен. 11, 2024

Язык: Английский

Процитировано

23
Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson's disease DOI Creative Commons
Alberto J. Espay,

Andrew Lees

Parkinsonism & Related Disorders, Год журнала: 2024, Номер 122, С. 106077 - 106077

Опубликована: Март 3, 2024

These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson's disease: (1) most brains from people without neurological symptoms have multiple pathologies; (2) neither type nor distribution correlate with disease severity or progression in disease; (3) aggregated α-synuclein form of bodies is not a space-occupying lesion but insoluble fraction its precursor, soluble monomeric α-synuclein; (4) spread passive, occurring by irreversible nucleation, active replication; and (5) low cerebrospinal fluid levels predict brain atrophy clinical progression. The transformation into may occur as response to biological, toxic, infectious stressors whose persistence perpetuates nucleation process, depleting normal eventually leading neuronal death. We propose testing loss-of-function synucleinopenia hypothesis evaluating neurodegenerative rescue effect replenishing α-synuclein.

Язык: Английский

Процитировано

17