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

The Protein Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 22, 2025

Язык: Английский

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Spuriously transcribed RNAs from CRISPR-sgRNA expression plasmids scaffold biomolecular condensate formation and hamper accurate genomic imaging

Nucleic Acids Research, Год журнала: 2025, Номер 53(6)

Опубликована: Март 20, 2025

Abstract Clustered regularly interspaced short palindromic repeats (CRISPR)-based imaging tools that utilize fluorescently tagged single-guide RNAs (sgRNAs) have enabled versatile analysis of the dynamics single genomic loci, but accuracy may be hindered by nonspecific subnuclear probe accumulation, generating false-positive foci in cell nuclei. By examining subcellular localizations sgRNA expression plasmids, their RNA transcripts, and several RNA-binding proteins, we found spuriously transcribed (cryptic) produced are major contributors signals, independent scaffold design or effector (i.e. aptamer- oligonucleotide-based probes) used. These transcripts interact with paraspeckle core not plasmids NEAT1_2, to form nuclear bodies display liquid-like properties including sphericality, fusion competence, sensitivity 1,6-hexanediol. Transfecting transcription units cassettes), lacking plasmid backbones, reduces signals enhances accuracy. Overall, this study unveils previously undescribed activities cryptic presents an easy-to-adapt strategy can potentially improve precision CRISPR-based systems implement sgRNAs.

Язык: Английский

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Induced proximity to PML protects TDP-43 from aggregation via SUMO–ubiquitin networks

Nature Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 17, 2025

Abstract The established role of cytosolic and nuclear inclusions TDP-43 in the pathogenesis neurodegenerative disorders has multiplied efforts to understand mechanisms that control aggregation spurred searches for approaches limiting this process. Formation clearance aggregates are controlled by an intricate interplay cellular proteostasis systems involve post-translational modifications frequently rely on spatial control. We demonstrate attachment ubiquitin-like SUMO2 modifier compartmentalizes promyelocytic leukemia protein (PML) bodies limits response proteotoxic stress. Exploiting pathway through proximity-inducing recruitment PML triggers a SUMOylation–ubiquitylation cascade protecting from stress-induced insolubility. protective function is mediated ubiquitylation conjunction with p97 disaggregase. Altogether, we SUMO–ubiquitin networks protect cells insoluble propose functionalization as potential future therapeutic avenue countering aggregation.

Язык: Английский

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TDP-43 nuclear condensation and neurodegenerative proteinopathies

Trends in Neurosciences, Год журнала: 2024, Номер 47(11), С. 849 - 850

Опубликована: Сен. 25, 2024

Язык: Английский

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