Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging

Lechler, Marie C.; Crawford, Emily; Groh, Nicole; Widmaier, Katja; Jung, Raimund; Kirstein, Janine; Trinidad, Jonathan C.; Burlingame, Alma L.; David, Della

doi:10.1016/j.celrep.2016.12.033

Cited by 62 publications

(121 citation statements)

References 51 publications

(77 reference statements)

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“…21,22 We overexpressed 2 key stress-granule-related RBPs (sgRBPs) with LC prion-like domains, PAB-1, homolog of human polyadenylate-binding protein 1 (PABP-1) and TIAR-2, homolog of human T-cell-restricted intracellular antigen-1 (TIA-1) in C. elegans pharyngeal muscles. 20 Upon heat stress, both fluorescently-labeled proteins assembled into stress granules as expected. Importantly without exposing animals to additional stress, PAB-1 and TIAR-2 accumulated in stress-granule-like structures as well as large puncta in aged C. elegans.…”

Section: Introductionsupporting

confidence: 57%

“…Notably in double transgenics, TIAR-2 recruited PAB-1 preferentially into stress granule-like structures with age. 20 These results reveal that interactions between 2 RBPs with different aggregation propensities can change their aggregation patterns.…”

Section: Aberrant Interactions Between Rbps and Other Aggregation-promentioning

confidence: 84%

“…Importantly, we found that animals with higher levels of PAB-1 aggregation were smaller, less motileandshorterlivedthananimalswithoutaggregation. 20 These results demonstrate that aggregation of sgRBPs is potentially toxic and could accelerate the agingprocess.…”

Section: Introductionmentioning

confidence: 82%

“…10,12 Our data revealed that PAB-1 and TIAR-2 have very different aggregation patterns with age. 20 Significantly, TIAR-2 distribution in aged animals was remarkably reminiscent of stress granule assembly caused by heat shock in young animals whereas PAB-1 tended to form mostly large aggregates with age. Notably in double transgenics, TIAR-2 recruited PAB-1 preferentially into stress granule-like structures with age.…”

Section: Aberrant Interactions Between Rbps and Other Aggregation-promentioning

confidence: 90%

“…Notably, we and others have shown that several hundred proteins are highly prone to aggregate during normal aging in different model organisms. [15][16][17][18][19] In our recent study, 20 the proteomic analysis of the aggregating proteome from longlived C. elegans with reduced daf-2/insulin/IGF-1 receptor signaling highlighted a specific group of proteins namely RNA granule components. In particular we identified several stress granule components as well as 4 RBPs with LC prion-like domains thatbecamehighlyinsolublewithageincontrolanimals but not in long-lived animals.…”

Section: Introductionmentioning

confidence: 99%

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More stressed out with age? Check your RNA granule aggregation

Lechler

David

2017

Prion

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ABSTRACT. Low complexity (LC) prion-like domains are over-represented among RNAbinding proteins (RBPs) and contribute to the dynamic nature of RNA granules. Importantly, several neurodegenerative diseases are characterized by cytoplasmic "solid" aggregates formed by mainly nuclear RBPs harboring LC prion-like domains. Although RBP aggregation in disease has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. Our recent study revealed that RNA granule components including 2 key stress granule RBPs with LC prion-like domains, PAB-1 and TIAR-2, aggregate in aged Caenorhabditis elegans in the absence of disease. Here we present new evidence showing that sustained stress granule formation triggers RBP aggregation. In addition, we demonstrate that mild chronic stress during aging promotes mislocalization of nuclear RBPs. We discuss the consequences of aberrant interactions between age-related RBP aggregation and diseaseassociated RBP aggregation. In particular, we show that FUST-1 and PAB-1 co-localize in aberrant cytoplasmic accumulations. Significantly, long-lived animals with reduced insulin/IGF-1 signaling abrogate stress granule RBP aggregation through activation of the transcription factors HSF-1 and DAF-16. We evaluate the different mechanisms that could maintain dynamic Ó 2017 Deutsches Zentrum f€ ur Neurodegenerative Erkrankungen e. V. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 313 Prion, 11:313-322, 2017 Published with license by Taylor & Francis ISSN: 1933-68961933-690X online DOI: 10.1080/19336896.2017 stress granules. Together these findings highlight how changes with age could contribute to pathogenesis in neurodegenerative diseases and disruption of RNA homeostasis.

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Section: Introductionsupporting

confidence: 57%

Section: Aberrant Interactions Between Rbps and Other Aggregation-promentioning

confidence: 84%

Section: Introductionmentioning

confidence: 82%

Section: Aberrant Interactions Between Rbps and Other Aggregation-promentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

More stressed out with age? Check your RNA granule aggregation

Lechler

David

2017

Prion

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Targeting stress granules in neurodegenerative diseases: A focus on biological function and dynamics disorders

Fang,

Liu,

Huang

et al. 2023

BioFactors

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Stress granules (SGs) are membraneless organelles formed by eukaryotic cells in response to stress to promote cell survival through their pleiotropic cytoprotective effects. SGs recruit a variety of components to enhance their physiological function, and play a critical role in the propagation of pathological proteins, a key factor in neurodegeneration. Recent advances indicate that SG dynamic disorders exacerbate neuronal susceptibility to stress in neurodegenerative diseases (NDs) including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD) and Parkinson's disease (PD). Here, we outline the biological functions of SGs, highlight SG dynamic disorders in NDs, and emphasize therapeutic approaches for enhancing SG dynamics to provide new insights into ND intervention.

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Perillaldehyde alleviates polyQ‐induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans

Fang,

Liu,

Gao

et al. 2024

BioFactors

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Huntington's disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPRmt) activation and positively regulated expression of associated genes. In lgg‐1 RNAi C. elegans or C. elegans with UPRmt‐related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ‐induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPRmt. Moreover, we found that pharmacological and genetic activation of UPRmt generally protected C. elegans from polyQ‐induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH‐1, and serotonin synthesis and neurosecretion were required for PAE‐mediated UPRmt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ‐related diseases including HD, which is dependent on autophagy and cell‐non‐autonomous UPRmt activation.

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Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging

Cited by 62 publications

References 51 publications

More stressed out with age? Check your RNA granule aggregation

More stressed out with age? Check your RNA granule aggregation

Targeting stress granules in neurodegenerative diseases: A focus on biological function and dynamics disorders

Perillaldehyde alleviates polyQ‐induced neurodegeneration through the induction of autophagy and mitochondrial UPR in Caenorhabditis elegans

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