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

Harel, Itamar; Chen, Yiwen R.; Ziv, Inbal; Singh, Param Priya; Heinzer, Daniel; Navarro Negredo, Paloma; Goshtchevsky, Uri; Wang, Wei; Astre, Gwendoline; Moses, Eitan; McKay, Andrew; Machado, Ben E.; Hebestreit, Katja; Yin, Sifei; Sánchez Alvarado, Alejandro; Jarosz, Daniel F.; Brunet, Anne

doi:10.1016/j.celrep.2023.112787

Cited by 2 publications

(2 citation statements)

References 101 publications

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“…the therapeutic response of cancer stem cells 86 ), how lineage composition is modified in tumors by the aging microenvironment remains largely unknown 6 . The killifish immune system 38,87 is largely underexplored when compared to other, relatively well-studied hallmarks of aging in killifish, including deregulated nutrient sensing 88,89 , telomere atrrition 14,15 , and loss of protein homeostasis 45,90,91 . By exploring the contribution of mutation accumulation and immune functions to age-related cancer, we demonstrate that these aging hallmarks can promote cancer incidences.…”

Section: Discussionmentioning

confidence: 99%

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A genetic toolbox for the turquoise killifish identifies sporadic age-related cancer

Rozenberg

Atlan

Franěk

et al. 2023

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Using lineage tracing and fate mapping strategies to study vertebrate aging has lagged behind developmental studies, primarily due to of the relatively long lifespans of classical models. Here, we introduce theKillibow, an inducible transgenic model forin-vivomulticolor lineage tracing in the naturally short-lived turquoise killifish (N. furzeri). We demonstrate that Cre-mediated recombination in transgenic fish can generate robust and stochastic labeling that remains stable during aging and regeneration. In addition, to achieve inducible control of recombination, we either utilizein-vivoCre electroporation or use the tamoxifen system inKillibow-derived cells. To further enable transplantation assays, we establish the first immunocompromised killifish model by mutatingrag2. RNA sequencing reveals thatrag2mutants exhibit severely compromised expression of V(D)J recombination products, including immunoglobulins. Accordingly, we demonstrate that clearance of transplantedKillibow-derived cells is delayed inrag2recipients, and present a proof-of-principle for a KRASG12Dcancer model that is compatible with lineage tracing. Our platform provides the opportunity to examine tissue homeostasis, stem cell function, cancer dynamics, and tissue regeneration at unprecedented temporal resolution during vertebrate aging and disease.

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Section: Discussionmentioning

confidence: 99%

“…Tissues samples were processed as described previously 14,15,[106][107][108][109][110][111][112]17,19,20,51,88,91,104,105 . Briefly, fish were euthanized with 500 mg/l tricaine (MS222, #A5040, Sigma).…”

Section: Hematoxylin and Eosinmentioning

confidence: 99%

A genetic toolbox for the turquoise killifish identifies sporadic age-related cancer

Rozenberg

Atlan

Franěk

et al. 2023

Preprint

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Cognition-Associated Protein Structural Changes in a Rat Model of Aging are Related to Reduced Refolding Capacity

Tarbox,

Branch,

Fried

2024

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Cognitive decline during aging represents a major societal burden, causing both personal and economic hardship in an increasingly aging population. There are a few well-known proteins that can misfold and aggregate in an age-dependent manner, such as amyloid β and α-synuclein. However, many studies have found that the proteostasis network, which functions to keep proteins properly folded, is impaired with age, suggesting that there may be many more proteins that incur structural alterations with age. Here, we used limited-proteolysis mass spectrometry (LiP-MS), a structural proteomic method, to globally interrogate protein conformational changes in a rat model of cognitive aging. Specifically, we compared soluble hippocampal proteins from aged rats with preserved cognition to those from aged rats with impaired cognition. We identified several hundred proteins as having undergone cognition-associated structural changes (CASCs). We report that CASC proteins are substantially more likely to be nonrefoldable than non-CASC proteins, meaning they typically cannot spontaneously refold to their native conformations after being chemically denatured. The potentially cofounding variable of post-translational modifications is systematically addressed, and we find that oxidation and phosphorylation cannot significantly explain the limited proteolysis signal. These findings suggest that noncovalent, conformational alterations may be general features in cognitive decline, and more broadly, that proteins need not form amyloids for their misfolded states to be relevant to age-related deterioration in cognitive abilities.

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

Cited by 2 publications

References 101 publications

A genetic toolbox for the turquoise killifish identifies sporadic age-related cancer

A genetic toolbox for the turquoise killifish identifies sporadic age-related cancer

Cognition-Associated Protein Structural Changes in a Rat Model of Aging are Related to Reduced Refolding Capacity

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