Biology subjects

Rogers, A. N.

Publications and source records attributed to Rogers, A. N..

4 recordsLinked to original sources

bioRxiv2024

Neuronal CBP-1 is required for enhanced body muscle proteostasis in response to reduced translation downstream of mTOR

BackgroundThe ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress. Here, we investigate the role of specific tissues in mediating the cytoprotective effects of low translation. MethodsThis study uses genetic tools (transgenic C. elegans, RNA interference and gene expression analysis) as well as physiological assays (survival and paralysis assays) in order to better understand how specific tissues contribute to adaptive changes involving cellular cross-talk that enhance proteostasis under low translation conditions. ResultsWe use the C. elegans system to show that lowering translation in neurons or the germline increases heat shock gene expression and survival under conditions of heat stress. In addition, we find that low translation in these tissues protects motility in a body muscle-specific model of proteotoxicity that results in paralysis. Low translation in neurons or germline also results in increased expression of certain muscle regulatory and structural genes, reversing reduced expression normally observed with aging in C. elegans. Enhanced resilience to protein unfolding stress requires neuronal expression of cbp-1. ConclusionLow translation in either neurons or the germline orchestrate protective adaptation in other tissues, including body muscle.

genetics↗

bioRxiv2024

Roles of progranulin and FRamides in neural versus non-neural tissues on dietary restriction-related longevity and proteostasis in C. elegans

Dietary restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimers disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-like neuropeptide (flp) genes and the neuroprotective growth factor progranulin gene prgn-1 under dietary restriction in C. elegans. Here, we tested the effects of flp-5, flp-14, flp-15 and pgrn-1 on lifespan and proteostasis under both standard and dietary restriction conditions. We also tested and distinguished function based on their expression in either neuronal or non-neuronal tissue. Lowering the expression of pgrn-1 and flp genes selectively in neural tissue showed no difference in survival under normal feeding conditions nor under DR in two out of three experiments performed. Reduced expression of flp-14 in non-neuronal tissue showed decreased lifespan that was not specific to DR. With respect to proteostasis, a genetic model of DR from mutation of the eat-2 gene that showed increased thermotolerance compared to fully fed wild type animals demonstrated no change in thermotolerance in response to knockdown of pgrn-1 or flp genes. Finally, we tested effects on motility in a neural-specific model of proteotoxicity and found that neuronal knockdown of pgrn-1 and flp genes improved motility in early life regardless of diet. However, knocking these genes down in non-neuronal tissue had variable results. RNAi targeting flp-14 increased motility by day seven of adulthood regardless of diet. Interestingly, non-neuronal RNAi of pgrn-1 decreased motility under standard feeding conditions while DR increased motility for this gene knockdown by day seven (early mid-life). Results show that pgrn-1, flp-5, flp-14, and flp-15 do not have major roles in diet-related changes in longevity or whole-body proteostasis. However, reduced expression of these genes in neurons increases motility early in life in a neural-specific model of proteotoxicity, whereas knockdown of non-neuronal expression mostly increases motility in mid-life under the same conditions.

molecular biology↗

bioRxiv2019

Dietary restriction induces post-transcriptional regulation of longevity genes.

Dietary restriction increases lifespan through adaptive changes in gene expression. To understand more about these changes, we analyzed the transcriptome and translatome of C. elegans subjected to dietary restriction. Transcription of muscle regulatory and structural genes increased, while increased expression of amino acid metabolism and neuropeptide signaling genes was controlled at the level of translation. Evaluation of post-transcriptional regulation identified putative roles for RNA binding proteins, RNA editing, microRNA, alternative splicing, and nonsense mediated decay in response to nutrient limitation. Using RNA interference, we discovered several differentially expressed genes that regulate lifespan. We also found a compensatory role for translational regulation, which offsets dampened expression of a large subset of transcriptionally downregulated genes. Furthermore, 3 UTR editing and intron retention increase under dietary restriction and correlate with diminished translation, while trans-spliced genes are refractory to reduced translation efficiency compared to messages with the native 5 UTR. Finally, we find that smg-6 and smg-7, which are genes governing selection and turnover of nonsense mediated decay targets, are required for increased lifespan under dietary restriction.

genomics↗

bioRxiv2019

Translational regulation of non-autonomous mitochondrial stress response promotes longevity

Inhibition of mRNA translation delays aging, but the underlying mechanisms remain underexplored. Mutations in both DAF-2 (IGF-1 receptor) and RSKS-1 (ribosomal S6 kinase/S6K) cause synergistic lifespan extension in C. elegans. To understand the roles of S6K-mediated translational regulation in this process, we performed genome-wide translational profiling and genetic screens to identify genes that are not only regulated at the translational level in the daf-2 rsks-1 mutant, but also affect lifespan. Inhibition of CYC-2.1 (cytochrome c) in the germline significantly extends lifespan through non-autonomous activation of the mitochondrial unfolded protein response (UPRmt) and AMP-activated kinase (AMPK) in the metabolic tissue. Furthermore, the RNA-binding protein GLD-1-mediated translational repression of cytochrome c in the germline is important for the non-autonomous activation of UPRmt and synergistic longevity of the daf-2 rsks-1 mutant. Together, these results illustrate a translationally regulated non-autonomous mitochondrial stress response mechanism in the modulation of lifespan by insulin-like signaling and S6K. HighlightsO_LILongevity of the daf-2 rsks-1 mutant is mediated by translational repression of ribosomal proteins and CYC-2.1/cytochrome c. C_LIO_LIGermline inhibition of cyc-2.1 non-autonomously activates UPRmt and AMPK to extend lifespan. C_LIO_LIGLD-1 represses germline cyc-2.1 translation in the daf-2 rsks-1 mutant. C_LIO_LITranslational regulation of cyc-2.1 and UPRmt contribute to the synergistic longevity of the daf-2 rsks-1 mutant. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/533695v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@9f3ce7org.highwire.dtl.DTLVardef@576930org.highwire.dtl.DTLVardef@bb0c09org.highwire.dtl.DTLVardef@133ce4_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗