DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6313 - 6313

Опубликована: Март 28, 2023

Parkinson’s disease (PD) is the second most common neurodegenerative around world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in pathophysiology of PD. There growing evidence suggesting involved propagation cellular PD, leading to neuropathology under different conditions. Here, we reviewed current work on First, outlined causes Second, described potential pathways by which mediates neurotoxicity PD discussed precise mechanisms drive these processes damage. In addition, looked ahead interventions targeting repair. Finally, based status research, key problems need be addressed future research were proposed.

Язык: Английский

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α-Synuclein liquid condensates fuel fibrillar α-synuclein growth

Science Advances, Год журнала: 2023, Номер 9(33)

Опубликована: Авг. 16, 2023

α-Synuclein (α-Syn) aggregation into fibrils with prion-like features is intimately associated Lewy pathology and various synucleinopathies. Emerging studies suggest that α-Syn could form liquid condensates through phase separation. The role of these in disease remains elusive the interplay between unexplored, possibly due to difficulties triggering formation cells. To address this gap, we developed an assay allowing controlled assembly/disassembly cells studied them upon exposure preformed fibrillar polymorphs. Fibrils triggered evolution solid-like structures displaying growing needle-like extensions exhibiting pathological amyloid hallmarks. No such changes were elicited on did not undergo We, therefore, propose a model where within fuels exogenous seeds growth, thus speeding up propagation pathogenic aggregates.

Язык: Английский

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Copper drives prion protein phase separation and modulates aggregation

Science Advances, Год журнала: 2023, Номер 9(44)

Опубликована: Ноя. 3, 2023

Prion diseases are characterized by prion protein (PrP) transmissible aggregation and neurodegeneration, which has been linked to oxidative stress. The physiological function of PrP seems related sequestering redox-active Cu 2+ , dyshomeostasis is observed in disease brain. It unclear whether contributes aggregation, recently shown be mediated condensation. This study indicates that promotes condensation live cells at the cell surface vitro through copartitioning. Molecularly, inhibited β-structure hydrophobic residues exposure. Oxidation, induced H 2 O triggered liquid-to-solid transition PrP:Cu condensates promoted amyloid-like aggregation. In cells, overexpression C initially protected against cytotoxicity but led upon extended copper Our data suggest as a buffer for prevents toxicity can into prolonged

Язык: Английский

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Self-assembly coupled to liquid-liquid phase separation

PLoS Computational Biology, Год журнала: 2023, Номер 19(5), С. e1010652 - e1010652

Опубликована: Май 15, 2023

Liquid condensate droplets with distinct compositions of proteins and nucleic acids are widespread in biological cells. While it is known that such droplets, or compartments, can regulate irreversible protein aggregation, their effect on reversible self-assembly remains largely unexplored. In this article, we use kinetic theory solution thermodynamics to investigate the liquid-liquid phase separation structures well-defined sizes architectures. We find that, when assembling subunits preferentially partition into liquid robustness against traps maximum achievable assembly rates be significantly increased. particular, both range conditions leading productive corresponding increase by orders magnitude. analyze rate equation predictions using simple scaling estimates identify effects as a function relevant control parameters. These results may elucidate processes underlie normal cellular functions pathogenesis, suggest strategies for designing efficient bottom-up nanomaterials applications.

Язык: Английский

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Emerging experimental methods to study the thermodynamics of biomolecular condensate formation

The Journal of Chemical Physics, Год журнала: 2024, Номер 160(9)

Опубликована: Март 6, 2024

The formation of biomolecular condensates in vivo is increasingly recognized to underlie a multitude crucial cellular functions. Furthermore, the evolution highly dynamic protein into progressively less reversible assemblies thought be involved variety disorders, from cancer over neurodegeneration rare genetic disorders. There an increasing need for efficient experimental methods characterize thermodynamics condensate and that can used screening campaigns identify rationally design modifying compounds. Theoretical advances field are also identifying key parameters measured order obtain comprehensive understanding underlying interactions driving forces. Here, we review recent progress development quantitative study forces behind temporal condensates.

Язык: Английский

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