scholarly journals Virulence test using nematodes to prescreen Nocardia species capable of inducing neurodegeneration and behavioral disorders

2017 ◽  
Author(s):  
Bernardin-Souibgui Claire ◽  
Zoropogui Anthony ◽  
Voisin Jeremy ◽  
Ribun Sebastien ◽  
Vasselon Valentin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Behavioral Disorders ◽  
Dopaminergic Neuron ◽  
Neuronal Damage ◽  
Lung Infection ◽  
Nocardia Species ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Bacterial Dissemination

Background. Parkinson’s disease (PD) is a disorder characterized by dopaminergic neuron programmed cell death. The etiology of PD remains uncertain—some cases are due to selected genes associated with familial heredity, others are due to environmental exposure to toxic components, but over 90% of cases have a sporadic origin. Nocardia are Actinobacteria that can cause human diseases like nocardiosis. This illness can lead to lung infection or central nervous system (CNS) invasion in both immunocompromised and immunocompetent individuals. The main species involved in CNS are N. farcinica, N. nova, N. brasiliensis and N. cyriacigeorgica. Some studies have highlighted the ability of N. cyriacigeorgica to induce Parkinson’s disease-like symptoms in animals. Actinobacteria are known to produce a large variety of secondary metabolites, some of which can be neurotoxic. We hypothesized that neurotoxic secondary metabolite production and the onset of PD-like symptoms in animals could be linked. Methods. Here we used a method to screen bacteria that could induce dopaminergic neurodegeneration before performing mouse experiments. Results.The nematode Caenorhabditis elegans allowed us to demonstrate that Nocardia strains belonging to N. cyriacigeorgica and N. farcinica species can induce dopaminergic neurodegeneration. Strains of interest involved with the nematodes in neurodegenerative disorders were then injected in mice. Infected mice had behavioral disorders that may be related to neuronal damage, thus confirming the ability of Nocardia strains to induce neurodegeneration. These behavioral disorders were induced by N. cyriacigeorgica species (N. cyriacigeorgica GUH-2 and N. cyriacigeorgica 44484) and N. farcinica 10152. Discussion.We conclude that C. elegans is a good model for detecting Nocardia strains involved in neurodegeneration. This model allowed us to detect bacteria with high neurodegenerative effects and which should be studied in mice to characterize the induced behavioral disorders and bacterial dissemination.

scholarly journals Virulence test using nematodes to prescreen Nocardia species capable of inducing neurodegeneration and behavioral disorders

2017 ◽  
Author(s):  
Bernardin-Souibgui Claire ◽  
Zoropogui Anthony ◽  
Voisin Jeremy ◽  
Ribun Sebastien ◽  
Vasselon Valentin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Behavioral Disorders ◽  
Dopaminergic Neuron ◽  
Neuronal Damage ◽  
Lung Infection ◽  
Nocardia Species ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Bacterial Dissemination

Background. Parkinson’s disease (PD) is a disorder characterized by dopaminergic neuron programmed cell death. The etiology of PD remains uncertain—some cases are due to selected genes associated with familial heredity, others are due to environmental exposure to toxic components, but over 90% of cases have a sporadic origin. Nocardia are Actinobacteria that can cause human diseases like nocardiosis. This illness can lead to lung infection or central nervous system (CNS) invasion in both immunocompromised and immunocompetent individuals. The main species involved in CNS are N. farcinica, N. nova, N. brasiliensis and N. cyriacigeorgica. Some studies have highlighted the ability of N. cyriacigeorgica to induce Parkinson’s disease-like symptoms in animals. Actinobacteria are known to produce a large variety of secondary metabolites, some of which can be neurotoxic. We hypothesized that neurotoxic secondary metabolite production and the onset of PD-like symptoms in animals could be linked. Methods. Here we used a method to screen bacteria that could induce dopaminergic neurodegeneration before performing mouse experiments. Results.The nematode Caenorhabditis elegans allowed us to demonstrate that Nocardia strains belonging to N. cyriacigeorgica and N. farcinica species can induce dopaminergic neurodegeneration. Strains of interest involved with the nematodes in neurodegenerative disorders were then injected in mice. Infected mice had behavioral disorders that may be related to neuronal damage, thus confirming the ability of Nocardia strains to induce neurodegeneration. These behavioral disorders were induced by N. cyriacigeorgica species (N. cyriacigeorgica GUH-2 and N. cyriacigeorgica 44484) and N. farcinica 10152. Discussion.We conclude that C. elegans is a good model for detecting Nocardia strains involved in neurodegeneration. This model allowed us to detect bacteria with high neurodegenerative effects and which should be studied in mice to characterize the induced behavioral disorders and bacterial dissemination.

scholarly journals Virulence test using nematodes to prescreenNocardiaspecies capable of inducing neurodegeneration and behavioral disorders

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3823 ◽  
Author(s):  
Claire Bernardin Souibgui ◽  
Anthony Zoropogui ◽  
Jeremy Voisin ◽  
Sebastien Ribun ◽  
Valentin Vasselon ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Behavioral Disorders ◽  
Neurodegenerative Disorders ◽  
Dopaminergic Neuron ◽  
Neuronal Damage ◽  
Lung Infection ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Bacterial Dissemination

BackgroundParkinson’s disease (PD) is a disorder characterized by dopaminergic neuron programmed cell death. The etiology of PD remains uncertain—some cases are due to selected genes associated with familial heredity, others are due to environmental exposure to toxic components, but over 90% of cases have a sporadic origin.Nocardiaare Actinobacteria that can cause human diseases like nocardiosis. This illness can lead to lung infection or central nervous system (CNS) invasion in both immunocompromised and immunocompetent individuals. The main species involved in CNS areN. farcinica, N. nova,N. brasiliensisandN. cyriacigeorgica. Some studies have highlighted the ability ofN. cyriacigeorgicato induce Parkinson’s disease-like symptoms in animals. Actinobacteria are known to produce a large variety of secondary metabolites, some of which can be neurotoxic. We hypothesized that neurotoxic secondary metabolite production and the onset of PD-like symptoms in animals could be linked.MethodsHere we used a method to screen bacteria that could induce dopaminergic neurodegeneration before performing mouse experiments.ResultsThe nematodeCaenorhabditis elegansallowed us to demonstrate thatNocardiastrains belonging toN. cyriacigeorgicaandN. farcinicaspecies can induce dopaminergic neurodegeneration. Strains of interest involved with the nematodes in neurodegenerative disorders were then injected in mice. Infected mice had behavioral disorders that may be related to neuronal damage, thus confirming the ability ofNocardiastrains to induce neurodegeneration. These behavioral disorders were induced byN. cyriacigeorgicaspecies (N. cyriacigeorgicaGUH-2 andN. cyriacigeorgica44484) andN. farcinica10152.DiscussionWe conclude thatC. elegansis a good model for detectingNocardiastrains involved in neurodegeneration. This model allowed us to detect bacteria with high neurodegenerative effects and which should be studied in mice to characterize the induced behavioral disorders and bacterial dissemination.

scholarly journals Found in Translation: The Utility of C. elegans Alpha-Synuclein Models of Parkinson’s Disease

2019 ◽  
Vol 9 (4) ◽  
pp. 73 ◽  
Author(s):  
Anthony Gaeta ◽  
Kim Caldwell ◽  
Guy Caldwell
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Dopamine Neurons ◽  
Genetic Modifiers ◽  
Transgenic Expression ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Cellular Phenotypes ◽  
Functional Mechanisms

Parkinson’s Disease (PD) is the second-most common neurodegenerative disease in the world, yet the fundamental and underlying causes of the disease are largely unknown, and treatments remain sparse and impotent. Several biological systems have been employed to model the disease but the nematode roundworm Caenorhabditis elegans (C. elegans) shows unique promise among these to disinter the elusive factors that may prevent, halt, and/or reverse PD phenotypes. Some of the most salient of these C. elegans models of PD are those that position the misfolding-prone protein alpha-synuclein (α-syn), a hallmark pathological component of PD, as the primary target for scientific interrogation. By transgenic expression of human α-syn in different tissues, including dopamine neurons and muscle cells, the primary cellular phenotypes of PD in humans have been recapitulated in these C. elegans models and have already uncovered multifarious genetic factors and chemical compounds that attenuate dopaminergic neurodegeneration. This review describes the paramount discoveries obtained through the application of different α-syn models of PD in C. elegans and highlights their established utility and respective promise to successfully uncover new conserved genetic modifiers, functional mechanisms, therapeutic targets and molecular leads for PD with the potential to translate to humans.

scholarly journals α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease

2021 ◽  
Author(s):  
Merry Chen ◽  
Julie Vincent ◽  
Alexis Ezeanii ◽  
Saurabh Wakade ◽  
Shobha Yerigenahally ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Motor Deficit ◽  
Rodent Models ◽  
Neuron Degeneration ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Disease Mechanisms ◽  
The Brain

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the brain in a prion-like manner. While rodent models have recapitulated gut-to-brain α-synuclein transmission, animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first C. elegans models in which feeding with α-synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human α-synuclein expressed in the host. PFF acceleration of α-synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with α-synuclein monomer produced much milder effects. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, and enzymes involved in heparan sulfate proteoglycan biosynthesis, afforded protection from PFF-induced seeding of aggregation and toxicity, as well as dopaminergic neurodegeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.

scholarly journals Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity

2020 ◽  
Vol 117 (29) ◽  
pp. 17296-17307 ◽  
Author(s):  
An Phu Tran Nguyen ◽  
Elpida Tsika ◽  
Kaela Kelly ◽  
Nathan Levine ◽  
Xi Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitor ◽  
Late Onset ◽  
Neuronal Damage ◽  
Preclinical Model ◽  
Gtpase Activity ◽  
Kinase Inhibition ◽  
Dopaminergic Neurodegeneration ◽  
The Brain

Mutations inleucine-rich repeat kinase 2(LRRK2) are the most common cause of late-onset, autosomal-dominant familial Parkinson’s disease (PD). LRRK2 functions as both a kinase and GTPase, and PD-linked mutations are known to influence both enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage in culture models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models containing familial LRRK2 mutations often lack robust PD-like neurodegenerative phenotypes. Here, we develop a robust preclinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or administration of the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the robust destabilization of human LRRK2 protein in the brain relative to endogenous LRRK2. Our study further demonstrates that G2019S LRRK2-induced dopaminergic neurodegeneration critically requires normal GTPase activity, as hypothesis-testing mutations that increase GTP hydrolysis or impair GTP-binding activity provide neuroprotection although via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent preclinical model ofLRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

scholarly journals Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity

2019 ◽  
Author(s):  
An Phu Tran Nguyen ◽  
Elpida Tsika ◽  
Kaela Kelly ◽  
Nathan Levine ◽  
Xi Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Inhibitor ◽  
Late Onset ◽  
Neuronal Damage ◽  
Gtpase Activity ◽  
Adult Rats ◽  
Kinase Inhibition ◽  
Dopaminergic Neurodegeneration ◽  
Cellular Models

AbstractMutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson’s disease (PD) and represent the most common known cause of PD. LRRK2 can function as both a protein kinase and GTPase and PD-linked mutations are known to influence both of these enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage and toxicity in cellular models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models based upon familial LRRK2 mutations often lack the hallmark features of PD and robust neurodegenerative phenotypes in general. Here, we develop a robust pre-clinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of full-length human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or in-diet dosing with the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the selective and robust destabilization of human LRRK2 protein in the rat brain relative to endogenous LRRK2. Our study further demonstrates that dopaminergic neurodegeneration induced by G2019S LRRK2 critically requires normal GTPase activity. The introduction of hypothesis-testing mutations that increase GTP hydrolysis or impair GTP binding activity provide neuroprotection against G2019S LRRK2 via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegeneration in vivo via a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent model of LRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.

scholarly journals Mutations in C. elegans neuroligin-like glit-1, the apoptosis pathway and the calcium chaperone crt-1 increase dopaminergic neurodegeneration after 6-OHDA treatment

2017 ◽  
Author(s):  
Sarah-Lena Offenburger ◽  
Elisabeth Jongsma ◽  
Anton Gartner
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Dopaminergic Neurons ◽  
Apoptosis Pathway ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Cell Death Pathway ◽  
6 Hydroxydopamine

AbstractThe loss of dopaminergic neurons is a hallmark of Parkinson’s disease, the aetiology of which is associated with increased levels of oxidative stress. We used C. elegans to screen for genes that protect dopaminergic neurons against oxidative stress and isolated glit-1 (gliotactin (Drosophila neuroligin-like) homologue). Loss of the C. elegans neuroligin-like glit-1 causes increased dopaminergic neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), an oxidative- stress inducing drug that is specifically taken up into dopaminergic neurons. Furthermore, glit-1 mutants exhibit increased sensitivity to oxidative stress induced by H2O2 and paraquat. We provide evidence that GLIT-1 acts in the same genetic pathway as the previously identified tetraspanin TSP-17. After exposure to 6-OHDA and paraquat, glit-1 and tsp-17 mutants show almost identical, non-additive hypersensitivity phenotypes and exhibit highly increased induction of oxidative stress reporters. TSP-17 and GLIT-1 are both expressed in dopaminergic neurons. In addition, the neuroligin-like GLIT-1 is expressed in pharynx, intestine and several unidentified cells in the head. GLIT-1 is homologous, but not orthologous to neuroligins, transmembrane proteins required for the function of synapses. The Drosophila GLIT-1 homologue Gliotactin in contrast is required for epithelial junction formation. We report that GLIT-1 likely acts in multiple tissues to protect against 6-OHDA, and that the epithelial barrier of C. elegans glit-1 mutants does not appear to be compromised. We further describe that hyperactivation of the SKN-1 oxidative stress response pathway alleviates 6-OHDA-induced neurodegeneration. In addition, we find that mutations in the canonical apoptosis pathway and the calcium chaperone crt-1 cause increased 6-OHDA-induced dopaminergic neuron loss. In summary, we report that the neuroligin-like GLIT-1, the canonical apoptosis pathway and the calreticulin CRT-1 are required to prevent 6-OHDA-induced dopaminergic neurodegeneration.Author summaryNeurons use dopamine as a chemical messenger to mediate diverse behaviours. The gradual loss of dopaminergic neurons in specific brain areas is a hallmark of Parkinson’s disease. The increased occurrence of highly reactive oxygen radicals, also called oxidative stress, is assumed to contribute to the demise of dopaminergic neurons. In this study we searched for genes that protect dopaminergic neurons against oxidative stress. We used the nematode C. elegans, a well- characterised model organism whose dopamine signalling system is very similar to that of humans. When C. elegans is exposed to 6-hydroxydopamine, an oxidative stress-inducing compound, dopaminergic neurons gradually die. Our major findings include: (i) absence of the neuroligin-like gene glit-1 causes highly increased cell death of dopaminergic neurons after 6-OHDA exposure; (ii) GLIT-1 acts in a similar manner as the previously identified tetraspanin TSP-17; (iii) GLIT-1 and TSP-17 also protect C. elegans from other types of oxidative stress; and (iv) the programmed cell death pathway and a calcium chaperone protect dopaminergic neurons as well. Collectively, this study shows that apoptosis proteins, the calcium chaperone CRT-1 and the neuroligin-like GLIT-1 protect against neurodegeneration after oxidative stress exposure.

scholarly journals Tuning Hsp104 specificity to selectively detoxify α-synuclein

2020 ◽  
Author(s):  
Korrie L. Mack ◽  
Hanna Kim ◽  
Meredith E. Jackrel ◽  
JiaBei Lin ◽  
Jamie E. DeNizio ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substrate Specificity ◽  
Neurodegenerative Disease ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Aaa Protein ◽  
Target Effects

SummaryHsp104 is an AAA+ protein disaggregase that solubilizes and reactivates proteins trapped in aggregated states. We have engineered potentiated Hsp104 variants to mitigate toxic misfolding of α-synuclein, TDP-43, and FUS implicated in fatal neurodegenerative disorders. Though potent disaggregases, these enhanced Hsp104 variants lack substrate specificity, and can have unfavorable off-target effects. Here, to lessen off-target effects, we engineer substrate-specific Hsp104 variants. By altering Hsp104 pore loops that engage substrate, we disambiguate Hsp104 variants that selectively suppress α-synuclein toxicity but not TDP-43 or FUS toxicity. Remarkably, α-synuclein-specific Hsp104 variants emerge that mitigate α-synuclein toxicity via distinct ATPase-dependent mechanisms, involving α-synuclein disaggregation or detoxification of α-synuclein conformers without disaggregation. Importantly, both types of α-synuclein-specific Hsp104 variant reduce dopaminergic neurodegeneration in a C. elegans model of Parkinson’s disease more effectively than non-specific variants. We suggest that increasing the substrate specificity of enhanced disaggregases could be applied broadly to tailor therapeutics for neurodegenerative disease.

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