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; Negredo, Paloma Navarro; Goshtchevsky, Uri; Wang, Wei; Astre, Gwendoline; Moses, Eitan; McKay, Andrew; Machado, Ben E.; Hebestreit, Katja; Yin, Sifei; Alvarado, Alejandro Sánchez; Jarosz, Daniel F.; Brunet, Anne

doi:10.1101/2022.02.26.482115

Cited by 17 publications

(13 citation statements)

References 99 publications

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“…Principal component analysis showed reproducible detergent-based fractionation in adult and old brains (Figure S2B) and GO enrichment analysis confirmed the expected partitioning of cellular components as a function of detergent strength (Figure S2C and S2D). In agreement with previous findings from other species ( 11 , 89 ) and the spontaneous age-related accumulation of protein aggregates in killifish brain ( 5 – 7 ), we observed an overall increase of protein detergent-insolubility in old samples (Figure S2E). By comparing detergent insolubility profiles between adult and old brains (Figure S2F-G), we identified 410 protein groups changing detergent insolubility with aging (Figure S5D, Table S2).…”

Section: Discussionsupporting

confidence: 93%

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Di Fraia,

Marino,

Lee

et al. 2023

Preprint

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Protein homeostasis declines both in aging and neurodegenerative diseases, yet our understanding of how aging affects brain proteostasis is still limited. Here, we measured and integrated the effects of aging on the transcriptome, translatome, and multiple layers of the proteome in the brain of a short-lived killifish. We found that aging causes a decoupling between transcript and protein levels leading to, e.g., decreased abundance of proteins enriched in basic amino acids independent of mRNA changes. Chronic proteasome impairment in vivo induces aging signatures in lysosomes and mitochondria. However, it does not recapitulate the age-related decoupling between transcripts and proteins. Instead, increased translation pausing and reduced ribosome levels reprogram protein synthesis independently of transcription. These changes in protein biogenesis likely reduce the availability of key protein complexes and contribute to the remodeling of organelles in older brains.

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Section: Discussionsupporting

confidence: 93%

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Di Fraia,

Marino,

Lee

et al. 2023

Preprint

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“…This observation is further strengthened by the fact that DDX5 was recently shown to form cytoplasmic aggregates in the brains of old killifish and mice. When studied in a yeast‐based heterologous system, DDX5's prion‐like domain allowed these aggregates to propagate across many generations 98 …”

Section: Resultsmentioning

confidence: 99%

“…When studied in a yeast-based heterologous system, DDX5's prion-like domain allowed these aggregates to propagate across many generations. 98 Prion proteins are known to be involved in stress response, and helicases are particularly good candidates for actuators of prion-based response as they can integrate diverse inputs and activate diverse outputs. Helicases provide immediate access to genetically complex traits by influencing the activity of many genes at the same time-in consequence enabling phenotypic variation that might be necessary for survival in a changing environment.…”

Section: Overlap Of Enriched Go Terms Assigned To Prion Candidates Ac...mentioning

confidence: 99%

Conserved functions of prion candidates suggest a primeval role of protein self‐templating

et al. 2023

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Amyloid‐based prions have simple structures, a wide phylogenetic distribution, and a plethora of functions in contemporary organisms, suggesting they may be an ancient phenomenon. However, this hypothesis has yet to be addressed with a systematic, computational, and experimental approach. Here we present a framework to help guide future experimental verification of candidate prions with conserved functions to understand their role in the early stages of evolution and potentially in the origins of life. We identified candidate prions in all high‐quality proteomes available in UniProt computationally, assessed their phylogenomic distributions, and analyzed candidate‐prion functional annotations. Of the 27 980 560 proteins scanned, 228 561 were identified as candidate prions (~0.82%). Among these candidates, there were 84 Gene Ontology (GO) terms conserved across the three domains of life. We found that candidate prions with a possible role in adaptation were particularly well‐represented within this group. We discuss unifying features of candidate prions to elucidate the primeval roles of prions and their associated functions. Candidate prions annotated as transcription factors, DNA binding, and kinases are particularly well suited to generating diverse responses to changes in their environment and could allow for adaptation and population expansion into more diverse environments. We hypothesized that a relationship between these functions and candidate prions could be evolutionarily ancient, even if individual prion domains themselves are not evolutionarily conserved. Candidate prions annotated with these universally occurring functions potentially represent the oldest extant prions on Earth and are therefore excellent experimental targets.

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“…Tissues samples were processed as described previously [12][13][14][15][48][49][50][51][52][53][54][55][56][57][58][59] . Briefly, fish were euthanized with 500 mg/l tricaine (MS222, #A5040, Sigma).…”

Section: Hematoxylin and Eosinmentioning

confidence: 99%

A scalable platform for functional interrogation of peptide hormones in fish

Moses

Harel

2023

Preprint

Self Cite

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Fish display a remarkable diversity of life-history traits, including body size, age at maturity, and longevity. Although pituitary hormones are conserved mediators of life-history transitions, regulatory networks are less understood in fish. However, the relatively long life-cycles and germline-dependent maturation of classical fish models are less compatible with rapid exploration of adult physiology, particularly in females. Here, we describe a high-throughput platform that combines, for the first time, loss- and gain-of-function of peptide hormones in a naturally short-lived fish. As a proof-of-principle, we first manipulate growth by mutating growth hormone (gh1) in the turquoise killifish (N. furzeri). Next, to rescue growth defects, we designed a vector in which hormones are tagged by a self-cleavable fluorescent reporter, and are ectopically expressed using intramuscular electroporation. A single injection of agh1-T2A-GFPplasmid was sufficient to produce a stable expression of tag-free hormone and rescue growth phenotypes. This, in contrast to current practice for which multiple injections of recombinant hormones are required. We demonstrate the versatility of our platform by rescuing female sterility, which is induced by manipulating the follicle stimulating hormone (fshb). As killifish maturation is germline-independent, both sexes can be explored in genetic models with germline defects. Finally, we describe a doxycycline-inducible system for tunable expression control. Together, this platform significantly advances the state-of-the-art by allowing high-throughput functional dissection of distinct life-history strategies in fish. This method could be multiplexed to facilitate various applications, including optimizing commercially valuable traits in aquaculture, or screening pro-longevity hormonal interventions in aging.

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

Cited by 17 publications

References 99 publications

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Impaired biogenesis of basic proteins impacts multiple hallmarks of the aging brain

Conserved functions of prion candidates suggest a primeval role of protein self‐templating

A scalable platform for functional interrogation of peptide hormones in fish

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