TDP-43 nuclear retention is antagonized by hypo-phosphorylation of its C-terminus in the cytoplasm

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Янв. 28, 2025

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), in which TDP-43, nuclear RNA-binding protein, forms cytoplasmic inclusions. Here, we have developed robust and automated method to assess protein self-assembly the cytoplasm using microtubules as nanoplatforms. Importantly, analyzed specifically full-length TDP-43 its mRNA binding that are regulated by phosphorylation self-adhesive C-terminus, recipient pathological mutations. We show C-terminus prevents recruitment mRNA-rich stress granules only under acute conditions because low affinity for but not mild conditions. In addition, negatively turn promotes import. anticipate reducing may be an interesting strategy reverse depletion diseases.

Язык: Английский

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Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Май 8, 2025

Abstract Increased phosphorylation of TDP-43 is a pathological hallmark several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation roles remain incompletely understood. A variety techniques have been utilized to understand phosphorylation, kinase/phosphatase manipulation, phosphomimic variants, genetic, physical, or chemical inducement in cell cultures animal models, via analyses post-mortem human tissues. These studies produced conflicting results: suggesting incongruously that may either drive disease progression serve neuroprotective role. In this review, we explore regulators putative kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, TTBK2, phosphatases PP1, PP2A, PP2B, disease. Building on recent studies, also examine consequences pathology, especially related mislocalisation, liquid–liquid phase separation, aggregation, neurotoxicity. By comparing findings from various review highlights both discrepancies unresolved aspects understanding phosphorylation. We propose role site context dependent, includes subcellular degradation. further suggest greater consideration normal functions be perturbed warranted. This synthesis aims build towards comprehensive complex pathogenesis neurodegeneration. Graphical subject by dephosphorylation phosphatases, which variably impacts protein localisation, neurotoxicity diseases.

Язык: Английский

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Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses

Cells, Год журнала: 2025, Номер 14(10), С. 680 - 680

Опубликована: Май 8, 2025

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share common genes pathomechanisms referred to as the ALS-FTD spectrum. A hallmark of pathology is abnormal aggregation proteins, including Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated liposarcoma (FUS/TLS), dipeptide repeat proteins resulting from C9orf72 hexanucleotide expansions. Genetic mutations linked disrupt stability, phase separation, interaction networks, promoting misfolding insolubility. This review explores molecular mechanisms underlying ALS-FTD, with a particular focus on TDP-43, it represents main aggregated species inside pathological inclusions can also aggregate its wild-type form. Moreover, this describes protective activated by cells prevent aggregation, chaperones post-translational modifications (PTMs). Understanding these regulatory pathways could offer new insights into targeted interventions aimed at mitigating cell toxicity restoring cellular function.

Язык: Английский

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Molecular simulations of enzymatic phosphorylation of disordered proteins and their condensates

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Май 19, 2025

Abstract Condensation and aggregation of disordered proteins in cellular non-equilibrium environments are shaped decisively by enzymes. Enzymes called kinases phosphorylate proteins, consuming the chemical fuel ATP. Protein phosphorylation such as Casein kinase 1 delta (CK1 δ ) determines interactions neurodegeneration-linked TDP-43. Hyperphosphorylation TDP-43 CK1 may be a cytoprotective mechanism for neurons, but how interacts with protein condensates is not known. Molecular dynamics simulations hold promise to resolve interact their condensates, this shapes dynamics. In practice, it difficult verify whether implementations chemical-fuel driven coarse-grained thermodynamically consistent, which we address generally applicable automatic Markov state modeling approach. work, thus elucidate simulations, drivers phosphorylated leads dissolution upon hyperphosphorylation.

Язык: Английский

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