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

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4969 - 4969

Published: May 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.

Language: Английский

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Deciphering the Morphological Difference of Amyloid-β Fibrils in Familial and Sporadic Alzheimer’s Diseases

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(20), P. 8024 - 8033

Published: Oct. 9, 2024

The aggregation of amyloid-β (Aβ) into amyloid fibrils is the major pathological hallmark Alzheimer's disease (AD). Aβ can adopt a variety morphologies, relative populations which are recently found to be associated with different AD subtypes such as familial and sporadic (fAD sAD, respectively). two differ in their ages onset, AD-related genetic predispositions, dominant fibril morphologies. We postulate that these subtype-dependent morphology differences attributed intrinsic properties interacting molecules environment. Using atomistic discrete molecular dynamics simulations, we demonstrated fAD-dominant exhibited lower free-energy barrier for growth but also stability compared sAD-dominant morphology, resulting time-dependent population change consistent experimental observations. Additionally, studied effect Bri2 BRICHOS domain, an endogenous protein has been reported inhibit by preferential binding fibrils, one possible environmental factors. domain showed stronger than silico, suggesting more effective suppression formation. This result explains high cases normal functions. Genetic predisposition fAD, on other hand, might impair or overwhelm functions, leading fAD-associated morphology. Together, our computational findings provide theoretical framework elucidating entailed distinct

Language: Английский

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Influence of physicochemical conditions on liquid-liquid phase separation and stability of immunoglobulin Y for storage and application

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 306, P. 141393 - 141393

Published: Feb. 22, 2025

Language: Английский

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The Regulation of TDP-43 Structure and Phase Transitions: A Review

The Protein Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Language: Английский

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Emerging biophysical origins and pathogenic implications of amyloid oligomers

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 26, 2025

The amyloid hypothesis has been a leading narrative concerning the pathophysiological foundation of Alzheimer's and Parkinson's disease. At two ends lie functional protein monomers pathology-defining fibrils, while early stages aggregation are populated by polymorphic, transient neurotoxic oligomers. As structure activity oligomers intertwined, here we show arising from liquid-liquid phase separation β-barrel formation, their routes to neurodegeneration, role in cerebrovascular perturbation. Together, this Perspective converges on multifaceted oligomer-axis central pathological origin and, hence, treatment diseases. For decades, research disease dementia lacked unified framework. This explores convergence key oligomerization processes that drive neurodegeneration damage, aiming advance effective diagnosis

Language: Английский

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Peptide Self-Assembly into Amyloid Fibrils: Unbiased All-Atom Simulations

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(14), P. 3320 - 3328

Published: March 6, 2024

Protein self-assembly plays an important role in biological systems, accounting for the formation of mesoscopic structures that can be highly symmetric as capsid viruses or disordered molecular condensates exhibit a one-dimensional fibrillar morphology amyloid fibrils. Deposits latter tissues individuals with degenerative diseases like Alzheimer's and Parkinson's has motivated extensive efforts to understand sequence events their formation. These studies aim identify on-pathway intermediates may targets therapeutic intervention. This detailed knowledge fibril remains obscure, part due challenges experimental analyses these processes. However, progress is being achieved short peptides advances our ability perform completely unbiased all-atom simulations process. perspective discusses recent developments, implications, hurdles still need overcome further advance field.

Language: Английский

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Crowder Chain Length Variability and Excluded Volume Effect on the Phase Separation Behavior of Mucin

The Journal of Physical Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(42), P. 10505 - 10513

Published: Oct. 11, 2024

Phase separation within cellular membranes, a critical process underpinning diverse functions, is significantly influenced by transmembrane proteins. Therefore, elucidating the behavior of protein in its phase-separated state utmost importance. Our study explores mucin milieu, aiming to determine role crowder chain length and excluded volume phase separation. Confocal microscopy images demonstrate strong partitioning into condensed hydrophobic electrostatic interactions. Fluorescence recovery after photobleaching analysis revealed increased mobility presence shorter crowders, indicating dynamic phases. Excluded calculation using theoretical model emphasizes importance under crowded conditions. findings underscore ability phase-separate conditions, highlighting crucial enhancing our understanding involvement cancer progression.

Language: Английский

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Tailoring the Molecular Structure of 6-Gingerol for Targeting the Phase Separation in Human Lysozyme

The Journal of Physical Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(31), P. 8032 - 8041

Published: July 31, 2024

Human lysozyme undergoes a phase-separation process to form insoluble amyloid-architects that cause several pathologies including systemic amyloidosis. Here we have tailored 6-gingerol by extending its molecular framework with active functional groups specifically target phase-transition events. Aggregation assay revealed 4-aromatic moieties (MTV4) substantially suppressed the conversion of low-density liquid phase (LDLP) solid-phase structured amyloids. The data obtained from biophysical, computational, and microscopic imaging tools suggest direct intervention MTV4 liquid–liquid separation. CD was able retain native conformation lysozyme. Both biomolecular computational reveal interference aggregation-prone hydrophobic stretches within lysozyme, thereby retaining structure reversing misfolded intermediates monomers. Also, induce rapid dissolution preformed-toxic amyloid fibrils. These results reinforce importance aromatic–aromatic interaction in preventing human

Language: Английский

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Liquid-liquid phase separation as triggering factor of fibril formation

Progress in molecular biology and translational science, Journal Year: 2024, Volume and Issue: unknown, P. 143 - 182

Published: Jan. 1, 2024

Language: Английский

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TDP-43 Promotes Amyloid-Beta Toxicity by Delaying Fibril Maturation via Direct Molecular Interaction

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(15), P. 2936 - 2953

Published: July 29, 2024

Amyloid-β (Aβ) is a peptide that undergoes self-assembly into amyloid fibrils, which compose the hallmark plaques observed in Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) with mislocalization and aggregation implicated amyotrophic lateral sclerosis other neurodegenerative diseases. Recent work suggests TDP-43 may interact Aβ, inhibiting formation of fibrils worsening AD pathology, but molecular details their interaction remain unknown. Using all-atom discrete dynamics simulations, we systematically investigated direct between Aβ TDP-43. We found monomers were able to bind near flexible nuclear localization sequence N-terminal domain (NTD) TDP-43, adopting β-sheet rich conformations promoted by interaction. Furthermore, associated nucleic acid binding interface tandem RNA recognition motifs via electrostatic interactions. computational array method, strongest C-terminal be within amyloidogenic core region With experimental evidence suggesting NTD necessary for fibril growth, also simulated an Aβ40 seed. was strongly elongation surface seed extensive hydrogen bonding could diffuse along Our results suggest surface, thereby sterically blocking monomer addition, responsible experimentally inhibition growth. conclude promote toxicity stabilizing oligomeric state kinetically delaying maturation.

Language: Английский

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