The promises of neurodegenerative disease modeling

Lepesant, Jean‐Antoine

doi:10.1016/j.crvi.2015.06.018

Cited by 6 publications

(5 citation statements)

References 54 publications

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“…The problem of neurodegeneration remains a pressing public health concern and a biologic black box [1,2]. Age-related neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia [FTD, the clinical disorder resulting from frontotemporal lobar degeneration (FTLD) [3]], and Huntington’s disease (HD) lead to cell death within the central nervous system (CNS) and progressive CNS dysfunction [4–9].…”

Section: Protein Misfolding Unites Diverse Neurodegenerative Diseasesmentioning

confidence: 99%

RNA-binding proteins with prion-like domains in health and disease

Harrison

Shorter

2017

Biochemical Journal

368

424

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Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribo-nucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.

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Section: Protein Misfolding Unites Diverse Neurodegenerative Diseasesmentioning

confidence: 99%

RNA-binding proteins with prion-like domains in health and disease

Harrison

Shorter

2017

Biochemical Journal

368

424

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“…Thus, the human orthologs of SWS NTE protein, is fully functional when expressed in flies [26]. Moreover, it is known that the expression of mutant human proteins AРР, alphasynuclein, and others in wildtype flies individuals cause the formation of pathological structures and physiological changes [13,16]. These data prove that Drosophila is an adequate model for human neuroactive peptides study.…”

Section: Resultsmentioning

confidence: 94%

“…Considering the methodological and ethical issues associated with research on humans, it is recommended to use model objects such as Drosophila melanogaster. It is a good test system for primary screening because there are similarities in morphological, biochemical, and functio nal characteristics between pathological changes in the structure of the brain of neurodegenerative Drosophila mutants and humans suffering from neuropathies [10,16]. Almost all genes related to neurodegeneration in humans have orthologs in the Drosophila genome.…”

mentioning

confidence: 99%

New Nootropic Preparation From Blood Plasma (Adement): Lack of Therapeutic Influence on Drosophila Neurodegenerative Model

Matiytsiv¹,

Dronska²,

Makarenko³

2018

VLUBS

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Development and research of new neuroactive agents remain relevant because of neurodegenerative diseases incurability. We tested an experimental preparation created from the peptide blood components of Alzheimer's patients in remission period. It was assumed that this product contained autoneuroactive molecules that might have therapeutic or prophylactic potential. Experimental preparation was tested on Drosophila sws-dependent neurodegenerative model. One test system was presented by wild type Oregon R and sws 1 mutants; another one was presented by transgenic lines for UAS-GAL4 controlled knockdown of sws gene in glial cells. Adement and negative control BPAP (blood plasma components of Alzheimer's patients) were fed in two ways: for larvae or on adult stage. The effects of preparations were evaluated by the survival of tested flies. Flies with different genotypes, fed in different ways showed individual survival characteristics in each particular case. How ever, we did not detect any cases of survival increasing; conversely, in some cases Adement reduced survival. The results showed no influence or toxicity effect of Adement on both control individuals and flies with sws-dependent neurodegeneration.

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“…A final C. elegans research focus worth noting is the use of transgenic and mutant worm strains to model Alzheimer's, Parkinson's, and Huntington diseases and for the discovery of potential therapeutics to treat these disorders (Chen et al 2015;Lepesant 2015). Sleigh et al (2011) isolated and characterized a C. elegans strain with a mutation and phenotype that mimics a mild form of spinal muscular atrophy.…”

Section: Drug Screening and Discovery In C Elegansmentioning

confidence: 99%

Drug Discovery in Fish, Flies, and Worms

Strange

2016

ILAR J

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Nonmammalian model organisms such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the zebrafish Danio rerio provide numerous experimental advantages for drug discovery including genetic and molecular tractability, amenability to high-throughput screening methods and reduced experimental costs and increased experimental throughput compared to traditional mammalian models. An interdisciplinary approach that strategically combines the study of nonmammalian and mammalian animal models with diverse experimental tools has and will continue to provide deep molecular and genetic understanding of human disease and will significantly enhance the discovery and application of new therapies to treat those diseases. This review will provide an overview of C. elegans, Drosophila, and zebrafish biology and husbandry and will discuss how these models are being used for phenotype-based drug screening and for identification of drug targets and mechanisms of action. The review will also describe how these and other nonmammalian model organisms are uniquely suited for the discovery of drug-based regenerative medicine therapies.

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The promises of neurodegenerative disease modeling

Cited by 6 publications

References 54 publications

RNA-binding proteins with prion-like domains in health and disease

RNA-binding proteins with prion-like domains in health and disease

New Nootropic Preparation From Blood Plasma (Adement): Lack of Therapeutic Influence on Drosophila Neurodegenerative Model

Drug Discovery in Fish, Flies, and Worms

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