In silico docking of Novel Phytoalkaloid Camalexin in the Management of Benomyl Induced Parkinson's disease and its In vivo Evaluation by Zebrafish Model

2021 ◽  
Vol 20 ◽  
Author(s):  
Tamilanban T ◽  
Manasa K ◽  
Chitra V
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Aldehyde Dehydrogenase ◽  
Neuronal Degeneration ◽  
In Vivo Model ◽  
Zebrafish Model ◽  
Standard Drug ◽  
In Silico Docking ◽  
Dehydrogenase Enzyme

Background: Parkinson’s disease (PD) exhibits the extra pyramidal symptoms caused due to the dopaminergic neuronal degeneration in the substantia nigra of the brain and depletion of aldehyde dehydrogenase (ALDH) enzyme. Objective: This study was designed to enlighten the importance of Aldehyde dehydrogenase enzyme in protecting the dopamine levels in a living system. Camalexin, a potentially active compound has been evaluated for its dopamine enhancing and aldehyde dehydrogenase protecting role in pesticide induced Parkinson’s disease. Methods: AutoDock 4.2 software was employed to perform the docking simulations between the ligand camalexin and standard drugs Alda-1, Ropirinole with three proteins 4WJR, 3INL, 5AER. Consequently, the compound was evaluated for its in vivo neuroprotective role in zebrafish model by attaining Institutional Animal Ethical Committee permission. The behavioral assessments and catecholamine analysis in zebrafish were performed. Results: The Autodock result shows that the ligand camalexin has a lower binding energy (-3.84) that indicate higher affinity with the proteins when compared to the standard drug of proteins (-3.42). In zebrafish model, behavioral studies provided an evidence that camalexin helps in improvement of motor functions and cognition. The catecholamine assay has proved there is an enhancement in dopamine levels, as well as an improvement in aldehyde dehydrogenase enzyme also. Conclusion: The novel compound, camalexin, hence offers a protective role in Parkinson’s disease model by its interaction with neurochemical proteins and also in alternative in vivo model.

scholarly journals Machine learning discriminates a movement disorder in a zebrafish model of Parkinson's disease

2020 ◽  
Vol 13 (10) ◽  
pp. dmm045815 ◽  
Author(s):  
Gideon L. Hughes ◽  
Michael A. Lones ◽  
Matthew Bedder ◽  
Peter D. Currie ◽  
Stephen L. Smith ◽  
...  
Keyword(s):  
Machine Learning ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Movement Disorders ◽  
Molecular Mechanisms ◽  
Computational Method ◽  
Metabolic Reprogramming ◽  
Loss Of Function ◽  
Zebrafish Model

ABSTRACTAnimal models of human disease provide an in vivo system that can reveal molecular mechanisms by which mutations cause pathology, and, moreover, have the potential to provide a valuable tool for drug development. Here, we have developed a zebrafish model of Parkinson's disease (PD) together with a novel method to screen for movement disorders in adult fish, pioneering a more efficient drug-testing route. Mutation of the PARK7 gene (which encodes DJ-1) is known to cause monogenic autosomal recessive PD in humans, and, using CRISPR/Cas9 gene editing, we generated a Dj-1 loss-of-function zebrafish with molecular hallmarks of PD. To establish whether there is a human-relevant parkinsonian phenotype in our model, we adapted proven tools used to diagnose PD in clinics and developed a novel and unbiased computational method to classify movement disorders in adult zebrafish. Using high-resolution video capture and machine learning, we extracted novel features of movement from continuous data streams and used an evolutionary algorithm to classify parkinsonian fish. This method will be widely applicable for assessing zebrafish models of human motor diseases and provide a valuable asset for the therapeutics pipeline. In addition, interrogation of RNA-seq data indicate metabolic reprogramming of brains in the absence of Dj-1, adding to growing evidence that disruption of bioenergetics is a key feature of neurodegeneration.This article has an associated First Person interview with the first author of the paper.

scholarly journals Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Souvarish Sarkar ◽  
Farah Bardai ◽  
Abby L. Olsen ◽  
Kelly M. Lohr ◽  
Ying-Yi Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Mitochondrial Dynamics ◽  
Actin Dynamics ◽  
Human Neurons ◽  
Biochemical Analyses ◽  
And Function

Abstract Background Mutations in LRRK2 are the most common cause of familial Parkinson’s disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue. Methods We combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human α-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models. Results We demonstrate that Lrrk and α-synuclein interact to promote neuronal degeneration through convergent effects on the actin cytoskeleton and downstream dysregulation of mitochondrial dynamics and function. We find specifically that monomers and dimers of Lrrk efficiently sever actin and promote normal actin dynamics in vivo. Oligomerization of Lrrk, which is promoted by dominant Parkinson’s disease-causing mutations, reduces actin severing activity in vitro and promotes excess stabilization of F-actin in vivo. Importantly, a clinically protective Lrrk mutant reduces oligomerization and α-synuclein neurotoxicity. Conclusions Our findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson’s disease, α-synuclein and LRRK2, and suggest potential new approaches for therapy development.

Neuroprotective effects of the gliopeptide ODN in an in vivo model of Parkinson’s disease

2017 ◽  
Vol 75 (11) ◽  
pp. 2075-2091 ◽  
Author(s):  
Seyma Bahdoudi ◽  
Ikram Ghouili ◽  
Mansour Hmiden ◽  
Jean-Luc do Rego ◽  
Benjamin Lefranc ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
In Vivo Model ◽  
Neuroprotective Effects

scholarly journals Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage

2021 ◽  
Vol 22 (9) ◽  
pp. 4643
Author(s):  
Rafael Franco ◽  
Rafael Rivas-Santisteban ◽  
Gemma Navarro ◽  
Annalisa Pinna ◽  
Irene Reyes-Resina
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Transgenic Animals ◽  
Relevant Information ◽  
Protein Processing ◽  
Vesicular Trafficking ◽  
Common Denominator

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson’s disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.

scholarly journals Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson’s disease

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Meghan L. Bucher ◽  
Caitlyn W. Barrett ◽  
Connor J. Moon ◽  
Amanda D. Mortimer ◽  
Edward A. Burton ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Dopamine Metabolism ◽  
In Vivo Model ◽  
Adult Rats ◽  
Adeno Associated Virus ◽  
Pathogenic Mechanisms ◽  
Virus Serotype

AbstractThe catecholamine neurotransmitter dopamine has the potential to act as an endogenous neurotoxin when its vesicular sequestration is dysregulated. Despite postmortem analyses from patients with Parkinson’s disease that demonstrate decreased vesicular sequestration of dopamine with a corresponding increase in dopamine metabolism, dopamine’s contribution to nigrostriatal dopaminergic degeneration in Parkinson’s disease has been debated. Here, we present a new in vivo model demonstrating the induction of Parkinson’s disease-associated pathogenic mechanisms of degeneration resulting from acquired dysregulation of dopamine sequestration in nigrostriatal dopaminergic neurons in adult rats. Utilizing adeno-associated virus (serotype 2), viral-mediated small-hairpin RNA interference of endogenous vesicular monoamine transporter 2 (VMAT2) expression resulted in a loss of VMAT2 protein expression in transduced dopaminergic cell bodies in the substantia nigra with a corresponding loss of VMAT2 protein within the striatal terminals. The loss of VMAT2 resulted in an accumulation of cytosolic dopamine and subsequent increased dopamine metabolism, deficits in dopamine-mediated behaviors, and degeneration of nigrostriatal dopaminergic neurons that was rescued through reintroduction of exogenous VMAT2, demonstrating that the toxicity was specific to the loss of VMAT2. Analysis of parkinsonian pathogenic mechanisms of degeneration identified oxidative damage, activation of Parkinson’s disease-associated kinase LRRK2, and the formation of aberrant α-synuclein. This model demonstrates that a progressive acquired loss of VMAT2 expression in adulthood is sufficient to induce Parkinson’s disease-associated pathogenic mechanisms of degeneration and provides a new model to further investigate the consequences of cytosolic dopamine.

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