Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(3)

Опубликована: Март 1, 2025

Abstract In Alzheimer's disease (AD), tau undergoes abnormal post‐translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy – targeted protein recently emerged as a modality in drug discovery where bifunctional molecules bring target close to machinery promote clearance. Since 2016, this has been applied pathologies attracted broad interest academia pharmaceutical industry. However, systematic review recent studies on mechanisms is lacking. Here we (the ubiquitin–proteasome system autophagy–lysosome pathway), their dysfunction AD, tau‐targeted degraders, such proteolysis‐targeting chimeras autophagy‐targeting chimeras. We emphasize need for continuous exploration provide future perspective developing encouraging researchers work treatment options AD patients. Highlights Post‐translational modifications, aggregation, mutations affect degradation. vicious circle exists between impaired pathologies. Ubiquitin plays an important role complex pathways. Tau‐targeted degraders promising strategies novel treatment.

Язык: Английский

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Protein-Based Degraders: From Chemical Biology Tools to Neo-Therapeutics

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

The nascent field of targeted protein degradation (TPD) could revolutionize biomedicine due to the ability degrader molecules selectively modulate disease-relevant proteins. A key limitation broad application TPD is its dependence on small-molecule ligands target proteins interest. This leaves unstructured or those lacking defined cavities for binding out scope many technologies. use proteins, peptides, and nucleic acids (otherwise known as "biologics") protein-targeting moieties in degraders addresses this limitation. In following sections, we provide a comprehensive critical review studies that have used peptides mediate hence functional control otherwise challenging targets. We describe existing platforms protein/peptide-based ligand identification drug delivery systems might be exploited biologic-based degraders. Throughout Review, underscore successes, challenges, opportunities using protein-based chemical biology tools spur discoveries, elucidate mechanisms, act new therapeutic modality.

Язык: Английский

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Genetically-encoded targeted protein degradation technology to remove endogenous condensation-prone proteins and improve crop performance

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

Опубликована: Янв. 29, 2025

Effective modulation of gene expression in plants is achievable through tools like CRISPR and RNA interference, yet methods for directly modifying endogenous proteins remain lacking. Here, we identify the E3 ubiquitin ligase E3TCD1 develope a Targeted Condensation-prone-protein Degradation (TCD) strategy. The X-E3TCD1 fusion protein acts as genetically engineered degrader, selectively targeting prone to condensation. For example, transgenic with Teosinte branched 1 (TB1) degrades native TB1 protein, resulting increased tiller numbers rice. Additionally, conditional degradation negative defense regulator Early Flowering 3 via pathogen-responsive ProTBF1-uORFsTBF1 cassette enhances rice blast resistance without affecting flowering time absence pathogen. Unlike prevailing targeted strategies, TCD system does not rely on small molecules, antibodies, or genetic knock-in tags, demonstrating its promise transgene-based approach optimizing crop performance.

Язык: Английский

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Organic solvents and neurodegenerative diseases: Exploring a possible link

Advances in neurotoxicology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Designed peptide binders and nanobodies as PROTAC starting points for targeted degradation of PCNA and BCL6

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 142667 - 142667

Опубликована: Март 1, 2025

Язык: Английский

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Inhibition of tau neuronal internalization using anti-tau single domain antibodies

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

Опубликована: Апрель 2, 2025

In Alzheimer's disease, tau pathology spreads across brain regions as the disease progresses. Intracellular can be released and taken up by nearby neurons. We evaluated single domain anti-tau antibodies, also called VHHs, inhibitors of internalization. identified three VHH uptake: A31, H3-2, Z70mut1. These VHHs compete with membrane protein LRP1, a major receptor mediating neuronal uptake tau. A31 Z70mut1 bind to microtubule binding repeats, which are involved in interaction LRP1. H3-2 is only from our library that reduces internalization both monomeric fibrils. binds C-terminal epitope high affinity. Its three-dimensional structure complex peptide reveals unique mode VHH-swapped dimer. interesting tools study prion-like propagation tauopathies potentially develop novel biotherapies.

Язык: Английский

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Targeting neurodegenerative disease-associated protein aggregation with proximity-inducing modalities

Acta Pharmacologica Sinica, Год журнала: 2025, Номер unknown

Опубликована: Апрель 7, 2025

Язык: Английский

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A No-Brainer! The Therapeutic Potential of TRIM Proteins in Viral and Central Nervous System Diseases

Viruses, Год журнала: 2025, Номер 17(4), С. 562 - 562

Опубликована: Апрель 14, 2025

Tripartite motif (TRIM) proteins comprise an important class of E3 ubiquitin ligases that regulate numerous biological processes including protein expression, cellular signaling pathways, and innate immunity. This ubiquitous participation in fundamental aspects biology has made TRIM a focus study many fields illuminated the negative impact they exert when functioning improperly. Disruption function been linked to success various pathogens separately occurrence development several neurodegenerative diseases, making appealing candidate for novel therapeutic approaches. Here, we review current findings on demonstrate their analogous properties distinct viral infection central nervous system (CNS) disorders. We also examine recent advancements drug targeted degradation as potential strategies TRIM-mediated treatments discuss implications these technologies have future research directions.

Язык: Английский

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Targeted Protein Degradation: From Basic Science to Therapeutic Applications

ACS Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 18, 2025

Targeted protein degradation (TPD) is a groundbreaking approach in molecular therapeutics, enabling the selective elimination of specific proteins by leveraging cell's own machinery. In November 2024, SMART Symposium titled "Targeted Protein Degradation: from basic science to therapeutic applications" offered comprehensive communication on cutting-edge chemical strategies and emerging clinical applications this rapidly advancing field.

Язык: Английский

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Targeted degradation of endogenous condensation-prone proteins improves crop performance

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 15, 2024

Abstract Effective methods, such as CRISPR and RNA interference, exist for modulating gene expression at DNA levels, but approaches directly modifying endogenous proteins remain lacking in plants. Here, we develop a targeted condensation-prone-protein degradation (TCD) strategy to eliminate proteins, particularly those prone condensation. We identify an E3 ligase, E3TCD1, that degrades itself selectively targets other when fused them. In rice, transgenic E3TCD1 fusions with Teosinte branched 1 Early flowering 3 (OsELF3) modulate tiller numbers times, respectively. The TCD system is also controllable. Using the Pro TBF1 -uORFs control cassette, can conditionally degrade negative defense regulator OsELF3 upon pathogen invasion, enhancing rice resistance without interfering time. This method, unlike animal-targeting strategies, does not rely on small molecules, antibodies, or genetic knock-ins, showing promise therapeutic avenue optimizing crop performance potentially addressing human diseases.

Язык: Английский

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