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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Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis

Science Advances, Journal Year: 2023, Volume and Issue: 9(31)

Published: Aug. 4, 2023

The cytoplasmic aggregation of TAR DNA binding protein-43 (TDP-43), also known as TDP-43 pathology, is the pathological hallmark amyotrophic lateral sclerosis (ALS). However, mechanism underlying mislocalization and subsequent remains unclear. Here, we show that dimerization/multimerization impaired in postmortem brains spinal cords patients with sporadic ALS N-terminal dimerization–deficient consists inclusion bodies motor neurons. Expression mutant Neuro2a cells induced pluripotent stem cell–derived neurons recapitulates such Nxf1-dependent aggregate formation, which induces seeding effects. Furthermore, TDP-DiLuc, a bimolecular luminescence complementation reporter assay, could detect decreased dimerization before changes caused by transcription inhibition linked to aberrant RNA metabolism ALS. These findings identified monomerization critical determinant inducing pathology

Language: Английский

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Lost in local translation: TDP-43 and FUS in axonal/neuromuscular junction maintenance and dysregulation in amyotrophic lateral sclerosis

Neuron, Journal Year: 2023, Volume and Issue: 111(9), P. 1355 - 1380

Published: March 23, 2023

Language: Английский

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Theory and Simulation of Multiphase Coexistence in Biomolecular Mixtures

Journal of Chemical Theory and Computation, Journal Year: 2023, Volume and Issue: 19(12), P. 3429 - 3445

Published: June 5, 2023

Biomolecular condensates constitute a newly recognized form of spatial organization in living cells. Although many are believed to as result phase separation, the physicochemical properties that determine behavior heterogeneous biomolecular mixtures only beginning be explored. Theory and simulation provide invaluable tools for probing relationship between molecular determinants, such protein RNA sequences, emergence phase-separated complex environments. This review covers recent advances prediction computational design phase-separate into coexisting phases. First, we efforts understand with hundreds or thousands species using theoretical models statistical approaches. We then describe progress developing analytical theories coarse-grained predict multiphase detail required make contact biophysical experiments. conclude by summarizing challenges ahead modeling inhomogeneous

Language: Английский

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Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation

JACS Au, Journal Year: 2023, Volume and Issue: 3(3), P. 834 - 848

Published: Feb. 24, 2023

Biomolecular condensation is involved in various cellular processes; therefore, regulation of crucial to prevent deleterious protein aggregation and maintain a stable environment. Recently, class highly charged proteins, known as heat-resistant obscure (Hero) was shown protect other client proteins from pathological aggregation. However, the molecular mechanisms by which Hero remain unknown. In this study, we performed multiscale dynamics (MD) simulations Hero11, protein, C-terminal low-complexity domain (LCD) transactive response DNA-binding 43 (TDP-43), under conditions examine their interactions with each other. We found that Hero11 permeates into condensate formed LCD TDP-43 (TDP-43-LCD) induces changes conformation, intermolecular interactions, TDP-43-LCD. also examined possible structures atomistic coarse-grained MD higher fraction disordered region tends assemble on surface condensates. Based simulation results, have proposed three for Hero11's regulatory function: (i) dense phase, TDP-43-LCD reduces contact shows faster diffusion decondensation due repulsive Hero11-Hero11 interactions. (ii) dilute saturation concentration increased, its conformation relatively more extended variant, induced attractive Hero11-TDP-43-LCD (iii) small condensates can contribute avoiding fusion The provide new insights biomolecular cells conditions.

Language: Английский

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CPSF6 regulates alternative polyadenylation and proliferation of cancer cells through phase separation

Cell Reports, Journal Year: 2023, Volume and Issue: 42(10), P. 113197 - 113197

Published: Sept. 30, 2023

Cancer cells usually exhibit shortened 3' untranslated regions (UTRs) due to alternative polyadenylation (APA) promote cell proliferation and migration. Upregulated CPSF6 leads a systematic prolongation of UTRs, but expression in tumors is typically higher than that healthy tissues. This contradictory observation suggests it necessary investigate the underlying mechanism by which regulates APA switching cancer. Here, we find can undergo liquid-liquid phase separation (LLPS), elevated LLPS associated with preferential usage distal poly(A) sites. CLK2, kinase upregulated cancer cells, destructs phosphorylating its arginine/serine-like domain. The reduction lead UTR cell-cycle-related genes accelerate proliferation. These results suggest LLPS, rather level, may be responsible for regulation cells.

Language: Английский

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GENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 20, 2024

Abstract Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop hierarchical domain decomposition scheme dynamic load balancing for heterogeneous biomolecular systems keep even after drastic changes particle distribution. These schemes applied the of intrinsically disordered protein (IDP) droplets. During fusion two droplets, find droplet shape correlate mixing IDP chains. Additionally, simulate achieving sizes comparable those observed microscopy. In our MD simulations, directly observe Ostwald ripening, phenomenon where small droplets dissolve molecules redeposit into larger methods have been implemented CGDYN GENESIS software, offering tool investigating mesoscopic using residue-level CG models.

Language: Английский

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Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 22, 2024

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that characterized by the cytoplasmic mislocalization aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), other nuclear RBPs detergent-insoluble aggregates cytoplasm degenerating neurons ALS/FTD is connected to pore dysfunction defects nucleocytoplasmic transport machinery. Recent advances suggest beyond their canonical role import protein cargoes, nuclear-import receptors (NIRs) can prevent reverse TDP-43, FUS, related restore localization function. Here, we showcase NIR family how they recognize cargo, drive import, chaperone linked ALS/FTD. We also discuss promise enhancing levels developing potentiated variants as therapeutic strategies for proteinopathies.

Language: Английский

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Stress-induced TDP-43 nuclear condensation causes splicing loss of function and STMN2 depletion

Cell Reports, Journal Year: 2024, Volume and Issue: 43(7), P. 114421 - 114421

Published: June 27, 2024

TDP-43 protein is dysregulated in several neurodegenerative diseases, which often have a multifactorial nature and may extrinsic stressors as "second hit." undergoes reversible nuclear condensation stressed cells including neurons. Here, we demonstrate that stress-inducible condensates are RNA-depleted, non-liquid assemblies distinct from the known bodies. Their formation requires oligomerization ATP inhibited by RNA. Using confocal nanoscanning assay, find amyotrophic lateral sclerosis (ALS)-linked mutations alter stress-induced changing its affinity to liquid-like ribonucleoprotein assemblies. Stress-induced transiently inactivates TDP-43, leading loss of interaction with binding partners function splicing. Splicing changes especially prominent persisting for STMN2 RNA, becomes rapidly depleted early during stress. Our results point pathological nucleus support therapeutic modulation stress response ALS.

Language: Английский

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Phosphomimetic substitutions in TDP-43’s transiently α-helical region suppress phase separation

Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(3), P. 361 - 373

Published: Jan. 4, 2024

Phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) is present within the aggregates several age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer's disease, to point that presence phosphorylated TDP-43 considered a hallmark some these diseases. The majority known phosphorylation sites detected in sclerosis degeneration patients located low-complexity domain (LCD), same has been shown be critical for liquid-liquid phase separation (LLPS). However, effect LCD on LLPS largely unexplored, any work done mainly focused near C-terminal end LCD. Here, we used phosphomimetic approach explore impact at residues S332 S333, transiently α-helical region have observed LLPS. Our turbidimetry fluorescence microscopy data demonstrate substitutions greatly suppress LLPS, solution NMR strongly suggest this least part due loss propensity variant. We also show S332D S333D slow droplet aging fibrillation protein. Overall, findings provide biophysical basis understanding fibrillation, suggesting 332 333 not necessarily directly related pathogenic process.

Language: Английский

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