Mechanisms and pathology of protein misfolding and aggregation

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(12), P. 912 - 933

Published: Sept. 8, 2023

Language: Английский

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Liquid-liquid Phase Separation of α-Synuclein: A New Mechanistic Insight for α-Synuclein Aggregation Associated with Parkinson's Disease Pathogenesis

Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 435(1), P. 167713 - 167713

Published: July 3, 2022

Language: Английский

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Wetting and complex remodeling of membranes by biomolecular condensates

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 22, 2023

Abstract Cells compartmentalize parts of their interiors into liquid-like condensates, which can be reconstituted in vitro. Although these condensates interact with membrane-bound organelles, potential for membrane remodeling and the underlying mechanisms such interactions are not well-understood. Here, we demonstrate that between protein - including hollow ones, membranes lead to remarkable morphological transformations provide a theoretical framework describe them. Modulation solution salinity or composition drives condensate-membrane system through two wetting transitions, from dewetting, broad regime partial wetting, complete wetting. When sufficient area is available, fingering ruffling interface observed, an intriguing phenomenon producing intricately curved structures. The observed morphologies governed by interplay adhesion, elasticity, interfacial tension. Our results highlight relevance cell biology, pave way design synthetic membrane-droplet based biomaterials compartments tunable properties.

Language: Английский

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Heterotypic electrostatic interactions control complex phase separation of tau and prion into multiphasic condensates and co-aggregates

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(2)

Published: Jan. 3, 2023

Biomolecular condensates formed via phase separation of proteins and nucleic acids are thought to perform a wide range critical cellular functions by maintaining spatiotemporal regulation organizing intracellular biochemistry. However, aberrant transitions implicated in multitude human diseases. Here, we demonstrate that two neuronal proteins, namely tau prion, undergo complex coacervation driven domain-specific electrostatic interactions yield highly dynamic, mesoscopic liquid-like droplets. The acidic N-terminal segment interacts electrostatically with the polybasic intrinsically disordered prion protein (PrP). We employed unique combination time-resolved tools encompass several orders magnitude timescales ranging from nanoseconds seconds. These studies unveil an intriguing symphony molecular events associated formation heterotypic comprising ephemeral, domain-specific, short-range nanoclusters. Our results reveal these can be tuned RNA stoichiometry-dependent manner resulting reversible, multiphasic, immiscible, ternary different morphologies core-shell nested This system exhibits typical three-regime behavior reminiscent other membraneless organelles including nucleolar condensates. also show upon aging, tau:PrP droplets gradually convert into solid-like co-assemblies sequestration persistent intermolecular interactions. vibrational Raman conjunction atomic force microscopy multi-color fluorescence imaging presence amorphous amyloid-like co-aggregates maturation. findings provide mechanistic underpinnings overlapping neuropathology involving PrP highlight broader biological role physiology disease.

Language: Английский

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Protein misfolding and amyloid nucleation through liquid–liquid phase separation

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(10), P. 4976 - 5013

Published: Jan. 1, 2024

Protein misfolding and amyloid aggregation, linked to neurodegenerative diseases, can result from liquid–liquid phase separation (LLPS) a subsequent liquid-to-solid transition. This represents LLPS as generic mechanism in nucleation.

Language: Английский

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Biomolecular condensates modulate membrane lipid packing and hydration

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 28, 2023

Membrane wetting by biomolecular condensates recently emerged as a key phenomenon in cell biology, playing an important role diverse range of processes across different organisms. However, understanding the molecular mechanisms behind condensate formation and interaction with lipid membranes is still missing. To study this, we exploited properties dyes ACDAN LAURDAN nano-environmental sensors combination phasor analysis hyperspectral lifetime imaging microscopy. Using glycinin model condensate-forming protein giant vesicles membranes, obtained vital information on process membrane wetting. Our results reveal that display differences water dynamics when changing salinity medium consequence rearrangements secondary structure protein. Remarkably, membrane-condensates well polymer indicated correlation between increased affinity enhanced packing. This demonstrated decrease dipolar relaxation all membrane-condensate systems, suggesting general mechanism to tune packing

Language: Английский

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Role of aberrant phase separation in pathological protein aggregation

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 82, P. 102678 - 102678

Published: Aug. 19, 2023

Language: Английский

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Targeting Biomolecular Condensation and Protein Aggregation against Cancer

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(14), P. 9094 - 9138

Published: June 28, 2023

Biomolecular condensates, membrane-less entities arising from liquid–liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated degenerative diseases cancer. This review thoroughly examines the dual nature of biomolecular spotlighting role cancer, particularly concerning p53 tumor suppressor. Given that over half malignant tumors possess mutations TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, not only misfolds but also forms aggregates analogous other protein-based amyloids, thus significantly influencing progression through loss-of-function, negative dominance, gain-of-function pathways. The exact molecular mechanisms underpinning mutant remain elusive. However, cofactors like nucleic acids glycosaminoglycans are known be critical players intersection between diseases. Importantly, we reveal molecules capable inhibiting aggregation curtail proliferation migration. Hence, targeting transitions solid-like amorphous states offers promising direction innovative diagnostics therapeutics.

Language: Английский

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Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(3), P. 839 - 839

Published: March 3, 2023

Parkinson’s disease, the second most common neurodegenerative disorder worldwide, is characterized by accumulation of protein deposits in dopaminergic neurons. These are primarily composed aggregated forms α-Synuclein (α-Syn). Despite extensive research on this only symptomatic treatments currently available. However, recent years, several compounds, mainly an aromatic character, targeting α-Syn self-assembly and amyloid formation have been identified. discovered different approaches, chemically diverse exhibit a plethora mechanisms action. This work aims to provide historical overview physiopathology molecular aspects associated with disease current trends small compound development target aggregation. Although these molecules still under development, they constitute important step toward discovering effective anti-aggregational therapies for disease.

Language: Английский

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The bacterial nucleoid-associated proteins, HU and Dps, condense DNA into context-dependent biphasic or multiphasic complex coacervates

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(5), P. 104637 - 104637

Published: March 23, 2023

The bacterial chromosome, known as its nucleoid, is an amorphous assemblage of globular nucleoprotein domains. It exists in a state phase separation from the cell's cytoplasm, irregularly-shaped, membrane-less, intracellular compartment. This (the nature which remains largely unknown) maintained through generations ad infinitum. Here, we show that HU and Dps, two most abundant nucleoid-associated proteins (NAPs) Escherichia coli, undergo spontaneous complex coacervation with different forms DNA/RNA, both individually each other's presence, to cause accretion compaction DNA/RNA into liquid-liquid separated condensates vitro. Upon mixing nucleic acids, HU-A HU-B form (a) biphasic heterotypic mixed helps lower Csat also (b) multiphasic condensates, demixed domains display contents Dps. We believe these modes are seen vitro can serve models for vivo relationships among NAPs nucleoids, involving local global variations relative abundances NAPs, especially subdomains characterized by differing grades separation. Our results clearly demonstrate some quantitative, qualitative, differences coacervating abilities DNA, potentially explaining (i) why E. coli has isoforms HU, (ii) changes Dps facilitate lag, logarithmic, stationary phases growth.

Language: Английский

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