Tissue-specific landscape of protein aggregation and quality control in an aging vertebrate

Developmental Cell, Год журнала: 2024, Номер 59(14), С. 1892 - 1911.e13

Опубликована: Май 28, 2024

Язык: Английский

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Rapid and precise genome engineering in a naturally short-lived vertebrate

eLife, Год журнала: 2023, Номер 12

Опубликована: Май 9, 2023

The African turquoise killifish is a powerful vertebrate system to study complex phenotypes at scale, including aging and age-related disease. Here, we develop rapid precise CRISPR/Cas9-mediated knock-in approach in the killifish. We show its efficient application precisely insert fluorescent reporters of different sizes various genomic loci order drive cell-type- tissue-specific expression. This method should allow establishment humanized disease models development cell-type-specific molecular probes for studying biology.

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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Can accelerated ageing models inform us on age‐related tauopathies?

Aging Cell, Год журнала: 2023, Номер 22(5)

Опубликована: Апрель 3, 2023

Ageing is the greatest risk factor of late-onset neurodegenerative diseases. In realm sporadic tauopathies, modelling process biological ageing in experimental animals forms foundation searching for molecular origin pathogenic tau and developing potential therapeutic interventions. Although prior research into transgenic models offers valuable lessons studying how mutations overexpression can drive pathologies, underlying mechanisms by which leads to abnormal accumulation remains poorly understood. Mutations associated with human progeroid syndromes have been proposed be able mimic an aged environment animal models. Here, we summarise recent attempts relation tauopathies using that carry syndromes, or genetic elements unrelated exceptional natural lifespans, a remarkable resistance ageing-related disorders.

Язык: Английский

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Exploring life-long tissue homeostasis through lineage tracing and cell transplantation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Май 1, 2023

Abstract Aging is accompanied by a progressive loss of tissue homeostasis, including declining stem-cell function and increased cancer susceptibility. The naturally short-lived African turquoise killifish has emerged as powerful system for investigating vertebrate aging. However, critical mass advanced genetic tools mechanistic studies been largely missing. Here, we develop the Killibow , multispectral transgenic line life-long lineage tracing, an immunocompromised rag2 mutant transplantation studies, mutants genomic instability (i.e. atm tp53 ). We performed series experiments using this platform, tracing following germline transplantation, identifying occurring age-related melanoma engraftment into mutants. Exploring tumor dynamics reveals intriguing interplay between adaptive immunity, evolutionarily conserved decline in immune functions. Together, toolkit streamlines investigation molecular mechanisms underlying homeostasis during aging disease.

Язык: Английский

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A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans

PLoS Biology, Год журнала: 2023, Номер 21(9), С. e3002284 - e3002284

Опубликована: Сен. 14, 2023

During aging, proteostasis capacity declines and distinct proteins become unstable can accumulate as protein aggregates inside outside of cells. Both in disease during selectively aggregate certain tissues not others. Yet, tissue-specific regulation cytoplasmic aggregation remains poorly understood. Surprisingly, we found that the inhibition 3 core quality control systems, namely chaperones, proteasome, macroautophagy, leads to lower levels age-dependent Caenorhabditis elegans pharyngeal muscles, but higher body-wall muscles. We describe a novel safety mechanism targets newly synthesized suppress their associated proteotoxicity. The relies on macroautophagy-independent lysosomal degradation involves several previously uncharacterized components intracellular pathogen response (IPR). propose this protective engages an anti-aggregation machinery targeting aggregating for degradation.

Язык: Английский

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A scalable and tunable platform for functional interrogation of peptide hormones in fish

eLife, Год журнала: 2023, Номер 12

Опубликована: Окт. 24, 2023

Pituitary hormones play a central role in shaping vertebrate life history events, including growth, reproduction, metabolism, and aging. The regulation of these traits often requires precise control hormone levels across diverse timescales. However, fine tuning circulating in-vivo has traditionally been experimentally challenging. Here, using the naturally short-lived turquoise killifish (N. furzeri), we describe high-throughput platform that combines loss- gain-of-function peptide hormones. Mutation three primary pituitary hormones, growth (gh1), follicle stimulating (fshb), thyroid (tshb), alters somatic reproduction. Thus, suggesting while undergoes extremely rapid maturity, it still relies on vertebrate-conserved genetic networks. As next stage, developed vector system which is tagged self-cleavable fluorescent reporter, ectopically expressed through intramuscular electroporation. Following single electroporation, phenotypes, such as are stably rescued for several months. Notably, demonstrate versatility this approach by multiplexing, dose-dependent, doxycycline-inducible systems to achieve tunable reversible expression. In summary, method relatively high-throughput, facilitates large-scale interrogation life-history strategies fish. Ultimately, could be adapted modifying aquaculture species exploring pro-longevity interventions.

Язык: Английский

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Amyloid Beta Precursor Protein contributes to brain aging and learning decline in short-lived turquoise killifish (Nothobranchius furzeri)

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

Опубликована: Окт. 12, 2024

Abstract Amyloid beta (Aβ) accumulation is associated with inflammation, neurodegeneration, and cognitive decline in the context of neurodegenerative diseases. However, its role during normal aging remains largely unexplored. In this study, we investigated natural impact Aβ precursor protein ( app ) on brain using a short-lived vertebrate model, turquoise killifish Nothobranchius furzeri ). We identified amyloid derivatives across different age groups found that pyroglutamated —a neurotoxic variant—accumulates intra-neuronally an age-dependent manner, co-localizing apoptosis marker TUNEL. To determine whether contributes to spontaneous aging, used CRISPR/Cas9 generate “amyloid a” appa knock-out strain. Notably, −/− mutants exhibited reduced cell death overall younger proteome, as well improved learning capacity old age. Taken together, broadly affects making it promising target for anti-aging interventions.

Язык: Английский

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A comprehensive atlas of the aging vertebrate brain reveals signatures of progressive proteostasis dysfunction

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июль 24, 2023

Aging and neurodegeneration entail diverse cellular molecular hallmarks. Here, we studied the effects of aging on transcriptome, translatome, multiple layers proteome in brain a short-lived killifish. We reveal that causes widespread reduction proteins enriched basic amino acids is independent mRNA regulation, it not due to impaired proteasome activity. Instead, identify cascade events where aberrant translation pausing leads reduced ribosome availability resulting remodeling independently transcriptional regulation. Our research uncovers vulnerable point brain's biology - biogenesis DNA/RNA binding proteins. This vulnerability may represent unifying principle connects various hallmarks, encompassing genome integrity biosynthesis macromolecules.

Язык: Английский

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Regulating translation in aging: from global to gene-specific mechanisms

EMBO Reports, Год журнала: 2024, Номер 25(12), С. 5265 - 5276

Опубликована: Ноя. 19, 2024

Язык: Английский

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