Amyloid-beta (Aβ1–42)-induced paralysis in Caenorhabditis elegans is reduced through NHR-49/PPARalpha

Leiteritz, Anne; Baumanns, Stefan; Wenzel, U.

doi:10.1016/j.neulet.2020.135042

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…100 μL of 10 μM Fenofibrate (Sigma F6020) in 0.1% DMSO was placed onto both NGM and slow‐killing plates before seeding with OP50 or PA14, respectively, as described above (Brandstädt et al, 2013; Leiteritz et al, 2020). Upon the drying and growth of the bacterial lawn, eggs were grown to L4 on either the Fenofibrate or 0.1% DMSO control plates and then were transferred to PA14 plates (similarly supplemented with Fibrate or DMSO) at L4 larval stage and survival monitored.…”

Section: Methodsmentioning

confidence: 99%

Cell nonautonomous roles of NHR‐49 in promoting longevity and innate immunity

et al. 2021

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Section: Methodsmentioning

confidence: 99%

Cell nonautonomous roles of NHR‐49 in promoting longevity and innate immunity

et al. 2021

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“…PPARα agonists such as Fibrates have been reported to increase lifespan and mitigate Amyloid β (Aβ)-induced paralysis in worms in an NHR-49-dependent manner (Leiteritz et al, 2020), strengthening the premise that the proteins share functional homology. Our observation here, on the role of NHR-49 in promoting immunity and its tissue-specific functions, are noteworthy in light of this and other similarities it shares with mammalian PPARα.…”

Section: The Conservation Of Nhr-49's Pro-immunity Functionmentioning

confidence: 99%

“…Fenofibrate supplementation assay: 100 µL of 10 µM Fenofibrate (Sigma F6020) in 0.1% DMSO were placed onto both NGM and slow-killing plates before seeding with OP50 or PA14, respectively, as described above (Brandstädt et al, 2013;Leiteritz et al, 2020). Upon the drying and growth of the bacterial lawn, eggs were grown to L4 on either the Fenofibrate or 0.1% DMSO control plates, then transferred to PA14 plates (similarly supplemented with Fibrate or DMSO) at L4 larval stage and survival monitored.…”

Section: Q-pcrsmentioning

confidence: 99%

NHR-49 Acts in Distinct Tissues to Promote Longevity versus Innate Immunity

Naim

Amrit

Ratnappan

et al. 2020

Preprint

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Aging and immunity are inextricably linked and many genes that extend lifespan also enhance immunoresistance. However, it remains unclear if longevity-enhancing factors modulate immunity and longevity by distinct or shared mechanisms. Here, we demonstrate that the Caenorhabditis elegans pro-longevity factor, NHR-49, also promotes resistance against Pseudomonas aeruginosa, but modulates immunity and longevity by spatially and mechanistically distinct mechanisms. Fenofibrate, an agonist of NHR-49’s mammalian functional homolog, PPARα, enhanced worm immunoresistance in an NHR-49-dependent manner. NHR-49 expression is increased by germline ablation, an intervention that extends lifespan, but lowered by pathogen exposure. NHR-49 acted in multiple somatic tissues to promote longevity, whereas, it’s pro-immunity function was mediated by neuronal expression. The canonical NHR-49 target genes, acs-2 and fmo-2, were upregulated by germline loss, but infection triggered fmo-2 downregulation and acs-2 upregulation. Interestingly, neither gene conferred resistance against Gram-negative Pseudomonas, unlike their reported roles in immunity against Gram-positive pathogens. Thus, NHR-49 is differentially regulated by interventions that bring about long-term changes (lifespan extension) vs. short-term stress (pathogen exposure) and in response it orchestrates distinct outputs, including pathogen-specific transcriptional programs. Overall, our study demonstrates the independent control of immunity and longevity by a conserved regulatory protein.

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“…Inhibited the Aβ-induced phenotype in a C. elegans AD model (Leiteritz et al, 2020). Raised Aβ-42 in APP transfected H4 cells (Kukar et al, 2005).…”

Section: Fenofibrate Pparα Agonist ↑↓mentioning

confidence: 99%

Finding Drug Repurposing Candidates for Neurodegenerative Diseases using Zebrafish Behavioral Profiles

Del Rosario Hernández,

Gore,

Kreiling

et al. 2023

Preprint

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Drug repurposing can accelerate drug development while reducing the cost and risk of toxicity typically associated with de novo drug design. Several disorders lacking pharmacological solutions and exhibiting poor results in clinical trials - such as Alzheimer's disease (AD) - could benefit from a cost-effective approach to finding new therapeutics. We previously developed a neural network model, Z-LaP Tracker, capable of quantifying behaviors in zebrafish larvae relevant to cognitive function, including activity, reactivity, swimming patterns, and optomotor response in the presence of visual and acoustic stimuli. Using this model, we performed a high-throughput screening of FDA-approved drugs to identify compounds that affect zebrafish larval behavior in a manner consistent with the distinct behavior induced by calcineurin inhibitors. Cyclosporine (CsA) and other calcineurin inhibitors have garnered interest for their potential role in the prevention of AD. We generated behavioral profiles suitable for cluster analysis, through which we identified 64 candidate therapeutics for neurodegenerative disorders.

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Amyloid-beta (Aβ1–42)-induced paralysis in Caenorhabditis elegans is reduced through NHR-49/PPARalpha

Cited by 7 publications

References 29 publications

Cell nonautonomous roles of NHR‐49 in promoting longevity and innate immunity

Cell nonautonomous roles of NHR‐49 in promoting longevity and innate immunity

NHR-49 Acts in Distinct Tissues to Promote Longevity versus Innate Immunity

Finding Drug Repurposing Candidates for Neurodegenerative Diseases using Zebrafish Behavioral Profiles

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