Identification of protein aggregates in the aging vertebrate brain with prion-like and phase-separation properties

Cell Reports, Год журнала: 2024, Номер 43(6), С. 112787 - 112787

Опубликована: Май 28, 2024

Protein aggregation, which can sometimes spread in a prion-like manner, is hallmark of neurodegenerative diseases. However, whether aggregates form during normal brain aging remains unknown. Here, we use quantitative proteomics the African turquoise killifish to identify protein that accumulate old vertebrate brains. These are enriched for RNA-binding proteins, notably ATP-dependent RNA helicase DDX5. We validate DDX5 forms aggregate-like puncta brains and mice. Interestingly, DDX5's domain allows these propagate across many generations yeast. In vitro, phase separates into condensates. Mutations abolish prion propagation also impair protein's ability separate. condensates exhibit enhanced enzymatic activity, but they mature inactive, solid aggregates. Our findings suggest with properties aging, could have implications age-dependency cognitive decline.

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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Long lifetime and tissue-specific accumulation of lamin A/C in Hutchinson–Gilford progeria syndrome

The Journal of Cell Biology, Год журнала: 2023, Номер 223(1)

Опубликована: Ноя. 15, 2023

LMNA mutations cause laminopathies that afflict the cardiovascular system and include Hutchinson-Gilford progeria syndrome. The origins of tissue specificity in these diseases are unclear as lamin A/C proteins broadly expressed. We show transcript levels not predictive protein across tissues use quantitative proteomics to discover context disease mutation each influence protein’s lifetime. Lamin A/C’s lifetime is an order magnitude longer aorta, heart, fat, where laminopathy pathology apparent, than liver intestine, which spared from disease. especially insoluble tissues, may limit degradation promote stability. Progerin even more long lived accumulates there over time. accumulation associated with impaired turnover hundreds abundant progeroid tissues. These findings identify a novel feature syndromes.

Язык: Английский

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Omics studies of nuclear protein aggregates in subcellular fractions reveals co- aggregation of RNA-binding proteins affecting cytosolic pathways

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Disease-associated RNA binding protein (RBP) aggregation is a hallmark of several age-related neurodegenerative diseases. How insoluble RBP aggregates leads to cellular dysfunction poorly understood. Here, we investigated the molecular mechanisms affected by PABPN1 aggregates. are nuclear, but regulates nuclear export mRNA. To explore consequences aggregates, performed sequencing and proteomic studies in subcellular fractions an inducible human muscle cell model. analyses revealed this model associated with reduced endogenous levels. Proteomic that most changes driven were cytoplasmic fraction, accounting for metabolism, differentiation biomechanics. Changes fraction small enriched RBPs. We show sequestration mRNA impaired translational efficiency. Our study suggests RBPs regulated both gain-of-function loss-of-function mechanisms, which relevant development therapeutics age-associated

Язык: Английский

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Alterations in protein quality control resulting in neurodegeneration and disease

Elsevier eBooks, Год журнала: 2025, Номер unknown, С. 123 - 175

Опубликована: Янв. 1, 2025

Язык: Английский

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DNA binding and mitotic phosphorylation protect polyglutamine proteins from assembly formation

Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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The thermodynamic hypothesis of protein aggregation

Molecular Aspects of Medicine, Год журнала: 2025, Номер 103, С. 101364 - 101364

Опубликована: Май 3, 2025

Язык: Английский

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A deeply conserved protease, acylamino acid-releasing enzyme (AARE), acts in ageing in Physcomitrella and Arabidopsis

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Янв. 17, 2023

Reactive oxygen species (ROS) are constant by-products of aerobic life. In excess, ROS lead to cytotoxic protein aggregates, which a hallmark ageing in animals and linked age-related pathologies humans. Acylamino acid-releasing enzymes (AARE) bifunctional serine proteases, acting on oxidized proteins. AARE found all domains life, albeit under different names, such as acylpeptide hydrolase (APEH/ACPH), acylaminoacyl peptidase (AAP), or (OPH). humans, malfunction is associated with pathologies, while their function plants less clear. Here, we provide detailed analysis genes the plant lineage an in-depth localization moss Physcomitrella angiosperm Arabidopsis. loss-of-function mutants have not been described for any organism so far. We generated analysed describe connection between function, aggregation proteins ageing, including accelerated developmental progression reduced life span. Our findings complement similar suggest unified concept may exist forms.

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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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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