C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins

Sandhof, Carl Alexander; Hoppe, Simon Oliver; Tittelmeier, Jessica; Nussbaum-Krammer, Carmen

doi:10.3390/biom10081188

Cited by 8 publications

(4 citation statements)

References 173 publications

(203 reference statements)

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“…We used C. elegans as a versatile in vivo model to evaluate the toxicity of R3Ags with or without drug treatment [35,36]. Drug-capped and drug-preinhibited R3Ags were administered to worms for 2 h, and the pharyngeal pumping was scored after an additional 2-24 h to determine whether the drug treatment affected aggregate-mediated toxicity in vivo (Fig.…”

Section: Drugs Protect C Elegans From R3ags-mediated Toxicitymentioning

confidence: 99%

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

et al. 2021

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Emerging experimental evidence suggests tau pathology spreads between neuroanatomically connected brain regions in a prion-like manner in Alzheimer's disease (AD). Tau seeding, the ability of prion-like tau to recruit and misfold na€ ıve tau to generate new seeds, is detected early in human AD brains before the development of major tau pathology. Many antitumour drugs have been reported to confer protection against neurodegeneration, supporting the repurposing of approved and experimental or investigational oncology drugs for AD therapy. In this study, we evaluated whether antitumour drugs that abrogate the generation of seed-competent aggregates of tau Repeat 3 (R3) domain peptides can prevent tau seeding and toxicity in Tau-RD P301S FRET Biosensor cells and Caenorhabditis elegans. We demonstrate that drugs that interact with the N-terminal VQI-VYK or the C-terminal region housing the Cys322 prevent R3 dimerisation, abolishing the generation of prion-like R3 seeds. Preformed R3 seeds (fibrils) capped with, or R3 seeds formed in the presence of VQIVYK-or Cys322-targeting drugs have a reduced potency to cause aggregation of na€ ıve tau in biosensor cells and protect worms from aggregate toxicity. These findings indicate that VQIVYK-or Cys322-targeting drugs may act as prophylactic agents against tau seeding.

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Section: Drugs Protect C Elegans From R3ags-mediated Toxicitymentioning

confidence: 99%

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

et al. 2021

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“…It is currently understood that the neurodegenerative disease-related proteins, especially TDP-43 (ALS), amyloid beta and tau (Alzheimer's disease), α-synuclein (Parkinson's disease, PD), and FUS (frontotemporal dementia, FTD), partially show some characteristics of misfolding prion proteins. In addition, the TDP-43 C. elegans model also showed that the autophagy-lysosome pathway is the prion-like transmission pathway of TDP-43 protein (Sandhof et al, 2020 ). Meanwhile, it was discovered that the regulation of autophagy or exocytosis/endocytosis can affect the transfer of these misfolded proteins (Tyson et al, 2017 ).…”

Section: C Elegans Modelsmentioning

confidence: 99%

Invertebrate genetic models of amyotrophic lateral sclerosis

Zhou,

2024

Front. Mol. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by the progressive death of motor neurons in the cerebral cortex, brain stem, and spinal cord. The exact mechanisms underlying the pathogenesis of ALS remain unclear. The current consensus regarding the pathogenesis of ALS suggests that the interaction between genetic susceptibility and harmful environmental factors is a promising cause of ALS onset. The investigation of putative harmful environmental factors has been the subject of several ongoing studies, but the use of transgenic animal models to study ALS has provided valuable information on the onset of ALS. Here, we review the current common invertebrate genetic models used to study the pathology, pathophysiology, and pathogenesis of ALS. The considerations of the usage, advantages, disadvantages, costs, and availability of each invertebrate model will also be discussed.

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“…The nematode worm, Caenorhabditis elegans ( C. elegans ), provides an excellent model system for understanding underlying disease biology in neurodegenerative conditions [ 20 , 27 , 28 ] and is a promising candidate for functional dissection of the complex genetic architecture of PD. Between 60-80% of human genes have orthologues in C. elegans [ 29 ] and its genome was the first of any multicellular organism to be completely sequenced [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

et al. 2021

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For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

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C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins

Cited by 8 publications

References 173 publications

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

Antitumour drugs targeting tau R3 VQIVYK and Cys322 prevent seeding of endogenous tau aggregates by exogenous seeds

Invertebrate genetic models of amyotrophic lateral sclerosis

Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

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