Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Biophysical analysis of drug efficacy on C. elegans models for neurodegenerative and neuromuscular diseases.

ABSTRACT: Caenorhabditis elegans has emerged as a powerful model organism for drug screening due to its cellular simplicity, genetic amenability and homology to humans combined with its small size and low cost. Currently, high-throughput drug screening assays are mostly based on image-based phenotyping with the focus on morphological-descriptive traits not exploiting key locomotory parameters of this multicellular model with muscles such as its thrashing force, a critical biophysical parameter when screening drugs for muscle-related diseases. In this study, we demonstrated the use of a micropillar-based force assay chip in combination with a fluorescence assay to evaluate the efficacy of various drugs currently used in treatment of neurodegenerative and neuromuscular diseases. Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson's Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model. These results underline the potential of our force assay chip in screening of potential drug candidates for the treatment of neurodegenerative and neuromuscular diseases when combined with a fluorescence assay in a two-dimensional analysis approach.

SUBMITTER: Sofela S

PROVIDER: S-EPMC8195402 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases.

Project description:AimsCells have developed quality control systems for protection against proteotoxicity. Misfolded and aggregation-prone proteins, which are behind the initiation and progression of many neurodegenerative diseases (ND), are known to challenge the proteostasis network of the cells. We aimed to explore the role of DNJ-27/ERdj5, an endoplasmic reticulum (ER)-resident thioredoxin protein required as a disulfide reductase for the degradation of misfolded proteins, in well-established Caenorhabditis elegans models of Alzheimer, Parkinson and Huntington diseases.ResultsWe demonstrate that DNJ-27 is an ER luminal protein and that its expression is induced upon ER stress via IRE-1/XBP-1. When dnj-27 expression is downregulated by RNA interference we find an increase in the aggregation and associated pathological phenotypes (paralysis and motility impairment) caused by human ?-amyloid peptide (A?), ?-synuclein (?-syn) and polyglutamine (polyQ) proteins. In turn, DNJ-27 overexpression ameliorates these deleterious phenotypes. Surprisingly, despite being an ER-resident protein, we show that dnj-27 downregulation alters cytoplasmic protein homeostasis and causes mitochondrial fragmentation. We further demonstrate that DNJ-27 overexpression substantially protects against the mitochondrial fragmentation caused by human A? and ?-syn peptides in these worm models.InnovationWe identify C. elegans dnj-27 as a novel protective gene for the toxicity associated with the expression of human A?, ?-syn and polyQ proteins, implying a protective role of ERdj5 in Alzheimer, Parkinson and Huntington diseases.ConclusionOur data support a scenario where the levels of DNJ-27/ERdj5 in the ER impact cytoplasmic protein homeostasis and the integrity of the mitochondrial network which might underlie its protective effects in models of proteotoxicity associated to human ND.

| S-EPMC3887457 | biostudies-literature

O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases.

Project description:O-GlcNAcylation is an abundant posttranslational modification in the brain implicated in human neurodegenerative diseases. We have exploited viable null alleles of the enzymes of O-GlcNAc cycling to examine the role of O-GlcNAcylation in well-characterized Caenorhabditis elegans models of neurodegenerative proteotoxicity. O-GlcNAc cycling dramatically modulated the severity of the phenotype in transgenic models of tauopathy, amyloid β-peptide, and polyglutamine expansion. Intriguingly, loss of function of O-GlcNAc transferase alleviated, whereas loss of O-GlcNAcase enhanced, the phenotype of multiple neurodegenerative disease models. The O-GlcNAc cycling mutants act in part by altering DAF-16-dependent transcription and modulating the protein degradation machinery. These findings suggest that O-GlcNAc levels may directly influence neurodegenerative disease progression, thus making the enzymes of O-GlcNAc cycling attractive targets for neurodegenerative disease therapies.

| S-EPMC3491483 | biostudies-literature

In vitro Models of Neurodegenerative Diseases.

Project description:Neurodegenerative diseases are progressive degenerative conditions characterized by the functional deterioration and ultimate loss of neurons. These incurable and debilitating diseases affect millions of people worldwide, and therefore represent a major global health challenge with severe implications for individuals and society. Recently, several neuroprotective drugs have failed in human clinical trials despite promising pre-clinical data, suggesting that conventional cell cultures and animal models cannot precisely replicate human pathophysiology. To bridge the gap between animal and human studies, three-dimensional cell culture models have been developed from human or animal cells, allowing the effects of new therapies to be predicted more accurately by closely replicating some aspects of the brain environment, mimicking neuronal and glial cell interactions, and incorporating the effects of blood flow. In this review, we discuss the relative merits of different cerebral models, from traditional cell cultures to the latest high-throughput three-dimensional systems. We discuss their advantages and disadvantages as well as their potential to investigate the complex mechanisms of human neurodegenerative diseases. We focus on in vitro models of the most frequent age-related neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease and prion disease, and on multiple sclerosis, a chronic inflammatory neurodegenerative disease affecting young adults.

| S-EPMC7247860 | biostudies-literature

Impact of Neurodegenerative Diseases on Drug Binding to Brain Tissues: From Animal Models to Human Samples.

Project description:Drug efficacy in the central nervous system (CNS) requires an additional step after crossing the blood-brain barrier. Therapeutic agents must reach their targets in the brain to modulate them; thus, the free drug concentration hypothesis is a key parameter for in vivo pharmacology. Here, we report the impact of neurodegeneration (Alzheimer's disease (AD) and Parkinson's disease (PD) compared with healthy controls) on the binding of 10 known drugs to postmortem brain tissues from animal models and humans. Unbound drug fractions, for some drugs, are significantly different between healthy and injured brain tissues (AD or PD). In addition, drugs binding to brain tissues from AD and PD animal models do not always recapitulate their binding to the corresponding human injured brain tissues. These results reveal potentially relevant implications for CNS drug discovery.

| S-EPMC6095788 | biostudies-other

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases.

Project description:Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.

| S-EPMC7078110 | biostudies-literature

Application of Urine-Derived Stem Cells to Cellular Modeling in Neuromuscular and Neurodegenerative Diseases.

Project description:Neuromuscular and neurodegenerative diseases are mostly modeled using genetically modified animals such as mice. However, animal models do not recapitulate all the phenotypes that are specific to human disease. This is mainly due to the genetic, anatomical and physiological difference in the neuromuscular systems of animals and humans. The emergence of direct and indirect human somatic cell reprogramming technologies may overcome this limitation because they enable the use of disease and patient-specific cellular models as enhanced platforms for drug discovery and autologous cell-based therapy. Induced pluripotent stem cells (iPSCs) and urine-derived stem cells (USCs) are increasingly employed to recapitulate the pathophysiology of various human diseases. Recent cell-based modeling approaches utilize highly complex differentiation systems that faithfully mimic human tissue- and organ-level dysfunctions. In this review, we discuss promising cellular models, such as USC- and iPSC-based approaches, that are currently being used to model human neuromuscular and neurodegenerative diseases.

| S-EPMC6915080 | biostudies-literature

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases.

Project description:There are over 50 lysosomal hydrolase deficiencies, many of which cause neurodegeneration, cognitive decline and death. In recent years, a number of broad innovative therapies have been proposed and investigated for lysosomal storage diseases (LSDs), such as enzyme replacement, substrate reduction, pharmacologic chaperones, stem cell transplantation, and various forms of gene therapy. Murine models that accurately reflect the phenotypes observed in human LSDs are critical for the development, assessment and implementation of novel translational therapies. The goal of this review is to summarize the neurodegenerative murine LSD models available that recapitulate human disease, and the pre-clinical studies previously conducted. We also describe some limitations and difficulties in working with mouse models of neurodegenerative LSDs.

| S-EPMC7174556 | biostudies-literature

In Silico Studies in Drug Research Against Neurodegenerative Diseases.

Project description:BackgroundNeurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease (PD), spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective degeneration of neurons and axons in the central nervous system (CNS) and constitute one of the major challenges of modern medicine. Computeraided or in silico drug design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays.MethodsIn the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches.ResultsDetailed analysis of the recently reported case studies revealed that the majority of them use a sequential combination of ligand and structure-based virtual screening techniques, with particular focus on pharmacophore models and the docking approach.ConclusionNeurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future.

| S-EPMC6080098 | biostudies-literature

Defective membrane remodeling in neuromuscular diseases: insights from animal models.

Project description:Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1), and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1) a common molecular pathway underlying these different neuromuscular diseases, and (2) tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches.

| S-EPMC3320571 | biostudies-literature

The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases.

Project description:The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington's Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-? signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homologues of genes that cause neurodegenerative disease at the NMJ have resulted in a better understanding of the roles of these proteins in vivo. These studies may shed light on the pathological mechanisms of these diseases, with implications for reduced BMP/TGF-? signaling in ALS, SMA and HD and increased signaling in HSP and MS.

| S-EPMC3095363 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data