scholarly journals Motor dysfunction in Drosophila melanogaster as a biomarker for developmental neurotoxicity

2021 ◽  
Author(s):  
Ana Cabrita ◽  
Alexandra A Medeiros ◽  
Telmo Pereira ◽  
António Sebastião Rodrigues ◽  
Michel Kranendonk ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Motor Neurons ◽  
Evaluation Method ◽  
Chemical Compounds ◽  
Developmental Neurotoxicity ◽  
Motor Dysfunction ◽  
Animal Testing ◽  
General Toxicity ◽  
Conventional Animal ◽  
Kinematic Approach

Humans interact with numerous chemical compounds with direct health implications, with several able to induce developmental neurotoxicity (DNT), which bear developmental, behavioral, and cognitive consequences from a young age. Current guidelines for DNT testing are notably costly, time consuming, and unsuitable for testing large numbers of chemicals. Therefore, there is a need for adequate alternatives to conventional animal testing for neurotoxicity and DNT. Here we show that detailed kinematic analysis can provide a strong indicator for DNT, using known (chlorpyrifos, CPS) or putative (β–N–methylamino–L–alanine, BMAA) neurotoxic compounds. Here we Drosophila melanogaster exposed to these compounds during development and evaluated for common general toxicity – notably developmental survival and pupal positioning, together with the FlyWalker system, a detailed adult kinematics evaluation method. At concentrations that do not induce general toxicity, the solvent DMSO had a significant effect on kinematic parameters. Nonetheless, CPS not only induced developmental lethality but also significantly impaired coordination in comparison to DMSO, altering 16 motor parameters, validating the usefulness of our kinematic approach. Interestingly, BMAA, although not lethal during development, induced a dose–dependent motor decay, targeting most parameters in young adult animals, phenotypically resembling normally aged, non-exposed flies. This effect was subsequently attenuated during ageing, indicating an adaptive response. Furthermore, BMAA induced an abnormal terminal differentiation of leg motor neurons, without inducing degeneration, underpinning the observed altered mobility phenotype. Overall, our results support our kinematic approach as a novel, highly sensitive and reliable tool to assess potential DNT of chemical compounds.

scholarly journals Motor Dysfunction in Drosophila Melanogaster as a Biomarker for Developmental Neurotoxicity

2021 ◽  
Author(s):  
Ana Cabrita ◽  
Alexandra Medeiros ◽  
Telmo Pereira ◽  
António Sebastião Rodrigues ◽  
Michel Kranendonk ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Developmental Neurotoxicity ◽  
Motor Dysfunction

scholarly journals Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Estela Area-Gomez ◽  
D. Larrea ◽  
T. Yun ◽  
Y. Xu ◽  
J. Hupf ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Cell Structure ◽  
Disease Onset ◽  
Point Of View ◽  
Motor Dysfunction ◽  
Cellular Processes ◽  
Progressive Muscle Weakness ◽  
Human Pathology ◽  
Lateral Sclerosis

AbstractMotor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.

A Toxicology Databank Based on Animal Safety Evaluation Studies of Pharmaceutical Compounds

1985 ◽  
Vol 4 (4) ◽  
pp. 447-459 ◽  
Author(s):  
C.E. Lumley ◽  
S.R. Walker
Keyword(s):  
Animal Studies ◽  
Evaluation Studies ◽  
Safety Evaluation ◽  
Pharmaceutical Compounds ◽  
Pharmaceutical Companies ◽  
Animal Testing ◽  
Testing Procedures ◽  
Conventional Animal ◽  
Computer Based ◽  
Animal Safety

1 Thirteen UK pharmaceutical companies have provided comprehensive toxicological data from repeated-dose animal safety evaluation studies of 74 pharmaceutical compounds. 2 These data comprise a unique toxicology database and this paper describes its establishment including the problems encountered, its current size with over 35 000 data fields, its content and potential value for retrospective analyses. 3 Increasing reliance on animal studies for predicting the safety of medicines in man necessitates a reappraisal of conventional animal testing procedures and better use of the considerable volume of data in the archives of regulatory authorities and pharmaceutical companies. This reappraisal may be achieved by the use of computer-based toxicology databanks.

scholarly journals Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model

2022 ◽  
Vol 5 (4) ◽  
pp. e202101193
Author(s):  
Megumi Akamatsu ◽  
Takenari Yamashita ◽  
Sayaka Teramoto ◽  
Zhen Huang ◽  
Janet Lynch ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Motor Neurons ◽  
Ampa Receptors ◽  
Motor Dysfunction ◽  
Rna Aptamers ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Efficacy And Safety ◽  
Intracerebroventricular Infusion ◽  
Sporadic Als ◽  
Als Patients

In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca2+-permeable, and are responsible for mediating abnormal Ca2+ influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor–mediated, abnormal Ca2+ influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.

scholarly journals Generation and Characterization of the Drosophila melanogaster paralytic Gene Knock-Out as a Model for Dravet Syndrome

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1261
Author(s):  
Andrea Tapia ◽  
Carlo N. Giachello ◽  
Martina Palomino-Schätzlein ◽  
Richard A. Baines ◽  
Máximo Ibo Galindo
Keyword(s):  
Drosophila Melanogaster ◽  
Motor Neurons ◽  
Sodium Current ◽  
Protein A ◽  
Dravet Syndrome ◽  
Genetic Modifiers ◽  
Membrane Excitability ◽  
Gene Encoding ◽  
Knock Out ◽  
New Treatments

Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. We have made a knock-out of the paralytic gene, the single Drosophila melanogaster gene encoding this type of protein, by homologous recombination. These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight, and walking tests. Moreover, they also manifested some cognitive alterations, such as anxiety and problems in learning. Electrophysiological analyses from larval motor neurons showed a decrease in cell capacitance and membrane excitability, while persistent sodium current increased. To detect alterations in metabolism, we performed an NMR metabolomic profiling of heads, which revealed higher levels in some amino acids, succinate, and lactate; and also an increase in the abundance of GABA, which is the main neurotransmitter implicated in Dravet syndrome. All these changes in the paralytic knock-out flies indicate that this is a good model for epilepsy and specifically for Dravet syndrome. This model could be a new tool to understand the pathophysiology of the disease and to find biomarkers, genetic modifiers and new treatments.

scholarly journals Sublethal Enteroviral Infection Exacerbates Disease Progression in an ALS Mouse Model

2021 ◽  
Author(s):  
Honglin Luo ◽  
Yuan Chao Xue ◽  
Huitao Liu ◽  
Yasir Mohamud ◽  
Amirhossein Bahreyni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Factor ◽  
Viral Infection ◽  
Motor Neurons ◽  
Immune Cell ◽  
Neuronal Damage ◽  
Motor Dysfunction ◽  
Sublethal Dose ◽  
Enteroviral Infection ◽  
Cvb3 Infection

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a fatalneurodegenerative disease of the motor neuron system associated with both genetic and environmental risk factors.Infection with enteroviruses, including poliovirus and coxsackievirus B3 (CVB3), has been proposed as a possible causal/risk factor for ALSdue to the evidence that enteroviruses can target motor neurons and establish a persistent infection in the central nervous system (CNS), and recent findings that enteroviral infection-induced molecular and pathologicalphenotypes closely resembleALS. However, a causal relationship has not yet been affirmed.Methods:Wild-type C57BL/6J and SOD1G85R ALS mice were intracerebroventricularly infected with a sublethal dose of CVB3 or sham-infected. For a subset of mice, ribavirin (a broad-spectrum anti-RNA viral drug) was given subcutaneously during the acute and/or chronic stage of infection. Following viral infection, general activity and survival were monitored daily for up to week 60. Starting atweek 20 post-infection (PI), motor functions were measured weekly. Mouse brains and/or spinal cords were harvested at day 10 and week 60 PI for histopathological evaluation of neurotoxicity, immunohistochemical staining of viral protein, neuroinflammatory/immune and ALS pathology markers, and NanoString and RT-qPCR analysis of inflammatory gene expression.Results: We found that sublethal infection (mimicking chronic infection) of SOD1G85R ALS mice with CVB3 resulted inearly onset and progressive motor dysfunction, andshortened lifespan, while similar viral infection in C57BL/6J, the background strain of SOD1G85R mice, did not significantly affect motor function and mortality as compared to mock infection within the timeframe of the current study (60 weeksPI).Furthermore, we showed that CVB3 infection led to a significant increase in proinflammatory gene expression and immune cell infiltration and induced ALS-related pathologies (i.e., TDP-43 pathology and neuronal damage) in the CNS of both SOD1G85R and C57BL/6J mice. Finally, wediscovered that early (day 1) but not late (day 15) administration of ribavirincould rescue ALS-like neuropathology and symptoms induced by CVB3 infection.Conclusions: Our study identifies a new risk factor that contributes to early onset and accelerated progression of ALS and offers opportunities for the development of novel targeted therapies.

scholarly journals The Drosophila melanogaster Cajal body

2006 ◽  
Vol 172 (6) ◽  
pp. 875-884 ◽  
Author(s):  
Ji-Long Liu ◽  
Christine Murphy ◽  
Michael Buszczak ◽  
Sarah Clatterbuck ◽  
Robyn Goodman ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Motor Neurons ◽  
Nuclear Body ◽  
Nuclear Bodies ◽  
Cajal Body ◽  
Small Nuclear Rna ◽  
Nuclear Rna ◽  
Survival Of Motor Neurons ◽  
And Function ◽  
Histone Locus

Cajal bodies (CBs) are nuclear organelles that are usually identified by the marker protein p80-coilin. Because no orthologue of coilin is known in Drosophila melanogaster, we identified D. melanogaster CBs using probes for other components that are relatively diagnostic for CBs in vertebrate cells. U85 small CB–specific RNA, U2 small nuclear RNA, the survival of motor neurons protein, and fibrillarin occur together in a nuclear body that is closely associated with the nucleolus. Based on its similarity to CBs in other organisms, we refer to this structure as the D. melanogaster CB. Surprisingly, the D. melanogaster U7 small nuclear RNP resides in a separate nuclear body, which we call the histone locus body (HLB). The HLB is invariably colocalized with the histone gene locus. Thus, canonical CB components are distributed into at least two nuclear bodies in D. melanogaster. The identification of these nuclear bodies now permits a broad range of questions to be asked about CB structure and function in a genetically tractable organism.

scholarly journals Screening for Developmental Neurotoxicity at the National Toxicology Program: The Future Is Here

2019 ◽  
Vol 167 (1) ◽  
pp. 6-14 ◽  
Author(s):  
Mamta Behl ◽  
Kristen Ryan ◽  
Jui-Hua Hsieh ◽  
Frederick Parham ◽  
Andrew J Shapiro ◽  
...  
Keyword(s):  
Web Application ◽  
Flame Retardants ◽  
Developmental Neurotoxicity ◽  
Animal Testing ◽  
Chemical Library ◽  
Regulatory Decision ◽  
Adverse Health Effects ◽  
National Toxicology Program

Abstract The National Toxicology Program (NTP) receives requests to evaluate chemicals with potential to cause adverse health effects, including developmental neurotoxicity (DNT). Some recent requests have included classes of chemicals such as flame retardants, polycyclic aromatic compounds, perfluoroalkyl substances, and bisphenol A analogs with approximately 20–50 compounds per class, many of which include commercial mixtures. However, all the compounds within a class cannot be tested using traditional DNT animal testing guideline studies due to resource and time limitations. Hence, a rapid and biologically relevant screening approach is required to prioritize compounds for further in vivo testing. Because neurodevelopment is a complex process involving multiple distinct cellular processes, one assay will unlikely address the complexity. Hence, the NTP sought to characterize a battery of in vitro and alternative animal assays to quantify chemical effects on a variety of neurodevelopmental processes. A culmination of this effort resulted in a NTP-hosted collaborative project with approximately 40 participants spanning across domains of academia, industry, government, and regulatory agencies; collaborators presented data on cell-based assays and alternative animal models that was generated using a targeted set of compounds provided by the NTP. The NTP analyzed the assay results using benchmark concentration (BMC) modeling to be able to compare results across the divergent assays. The results were shared with the contributing researchers on a private web application during the workshop, and are now publicly available. This article highlights the overview and goals of the project, and describes the NTP’s approach in creating the chemical library, development of NTPs data analysis strategy, and the structure of the web application. Finally, we discuss key issues with emphasis on the utility of this approach, and knowledge gaps that need to be addressed for its use in regulatory decision making.

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