Deletion of the <i>Caenorhabditis elegans</i> homologues of the <i>CLN3</i> gene, involved in human juvenile neuronal ceroid lipofuscinosis, causes a mild progeric phenotype

Voer, Gert de; Bent, Paola van der; Rodrigues, Ana João; Ommen, G.J.B. van; Peters, Dorien J.M.; Taschner, Peter E.M.

doi:10.1007/s10545-005-0125-7

Cited by 15 publications

(9 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18 Specifically, the XT7 strain had a median lifespan of 8.6 days, whereas wild-type N2 Bristol worms had a median lifespan of 11.2 days (23% reduction in XT7, Log-rank / Mantel-Cox test, p = 0.002). All five calcium channel antagonists tested led to an increase in the median lifespan, though only one drug, flunarizine, reached statistical significance based on the Log-rank Mantel-Cox test (p < 0.05).…”

Section: Resultsmentioning

confidence: 98%

“…18 N2 Bristol was the wild-type control strain studied, which was obtained as a stable line from the Caenorhabditis Genetics Center (CGC, www.wormbase.org). …”

Section: Methodsmentioning

confidence: 99%

“…Indeed, the nematode’s simple nervous system and short lifespan (median lifespan of wild-type N2 Bristol strain is ~2 weeks) serves as an intermediate model organism between yeast and mouse models. 18 Three homologues of CLN3 exist in C. elegans ( cln3-1 , cln3-2 , cln3-3 ), each of which is encoded by a different gene and expressed at different life stages and anatomical locations. 18 The cln-3 triple knockout strain is named XT7 [cln-3.2(gk41)I; cln-3.1(pk479)V; cln-3.3(gk118)V] and was previously shown to have a shortened lifespan.…”

Section: Introductionmentioning

confidence: 99%

“…18 Three homologues of CLN3 exist in C. elegans ( cln3-1 , cln3-2 , cln3-3 ), each of which is encoded by a different gene and expressed at different life stages and anatomical locations. 18 The cln-3 triple knockout strain is named XT7 [cln-3.2(gk41)I; cln-3.1(pk479)V; cln-3.3(gk118)V] and was previously shown to have a shortened lifespan. 18 Here, we used the XT7 complete cln-3 knockout strain to evaluate the therapeutic efficacy of calcium channel antagonist therapy in a living animal model of Batten disease.…”

Section: Introductionmentioning

confidence: 99%

“…18 The cln-3 triple knockout strain is named XT7 [cln-3.2(gk41)I; cln-3.1(pk479)V; cln-3.3(gk118)V] and was previously shown to have a shortened lifespan. 18 Here, we used the XT7 complete cln-3 knockout strain to evaluate the therapeutic efficacy of calcium channel antagonist therapy in a living animal model of Batten disease.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Flunarizine rescues reduced lifespan in CLN3 triple knock‐out Caenorhabditis elegans model of batten disease

Kwon

Falk

Bennett

2016

J of Inher Metab Disea

View full text Add to dashboard Cite

Summary CLN3 disease (Spielmeyer-Vogt-Sjogren-Batten disease, previously known as classic juvenile neuronal ceroid lipofuscinosis, NCL) is a pediatric-onset progressive neurodegenerative disease characterized by progressive vision loss, seizures, loss of cognitive and motor function, and early death. While no precise biochemical mechanism or therapies are known, the pathogenesis of CLN3 disease involves intracellular calcium accumulation that may trigger apoptosis. Our prior work in in vitro cell models of CLN3 deficiency suggested that FDA-approved calcium channel antagonists may have therapeutic value. To further evaluate the potential efficacy of this approach in an otherwise untreatable disorder, we sought to compare the therapeutic effects and underlying mechanisms in an animal model of CLN3 disease. Here, we used the well-characterized XT7 complete cln-3 knockout strain of C. elegans to evaluate the therapeutic efficacy of calcium channel antagonist therapy in a living animal model of Batten disease. Therapeutic effects of five calcium channel antagonists were evaluated on XT7 animal lifespan and in vivo mitochondrial physiology. Remarkably, maximal therapeutic efficacy in this model animal was observed with 1 μM flunarizine, the identical concentration previously identified in cell-based neuronal models of CLN3 disease. Specifically, flunarizine rescued the short lifespan of XT7 worms and prevented their pathophysiologic mitochondrial accumulation. These results confirm the treatment efficacy and dosing of flunarizine in cln-3 disease in a translational model organism. Clinical treatment trials in CLN3 human patients are now needed to test the dosing regimen and efficacy of flunarizine in individuals suffering with this otherwise untreatable and ultimately lethal neurologic disease.

show abstract

Section: Resultsmentioning

confidence: 98%

“…18 N2 Bristol was the wild-type control strain studied, which was obtained as a stable line from the Caenorhabditis Genetics Center (CGC, www.wormbase.org). …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Flunarizine rescues reduced lifespan in CLN3 triple knock‐out Caenorhabditis elegans model of batten disease

Kwon

Falk

Bennett

2016

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

Neuronale Zeroidlipofuszinosen (NCL) im Tiermodell

Rüther

2010

Ophthalmologe

View full text Add to dashboard Cite

Neuronal ceroid lipofuscinoses (NCL) are severe neurodegenerative diseases leading to early death. They belong to the group of lysosomal storage diseases. Epileptic seizures, dementia and motor deficits are frequent symptoms which are to be found prior to a total dismantling of personality and death. At present 10 subtypes of NCL can be distinguished from which the genetic defect is known in eight. The encoded proteins are soluble or membrane proteins whose function is still unclear in most cases. The investigation of the pathology and pathophysiology of NCL is highly dependent on animal models. Mouse models existing for all forms with a known genetic defect play a prominent role. Unfortunately, the retinal phenotype of some mouse models is milder than in humans rendering the appreciation of a positive therapeutic effect more difficult. Because of the severity of NCL, therapy strategies only established in a mouse model will be transferred to humans very quickly.

show abstract

Using C. elegans to Decipher the Cellular and Molecular Mechanisms Underlying Neurodevelopmental Disorders

2013

View full text Add to dashboard Cite

Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.

show abstract

Deletion of the Caenorhabditis elegans homologues of the CLN3 gene, involved in human juvenile neuronal ceroid lipofuscinosis, causes a mild progeric phenotype

Cited by 15 publications

References 41 publications

Flunarizine rescues reduced lifespan in CLN3 triple knock‐out Caenorhabditis elegans model of batten disease

Flunarizine rescues reduced lifespan in CLN3 triple knock‐out Caenorhabditis elegans model of batten disease

Neuronale Zeroidlipofuszinosen (NCL) im Tiermodell

Using C. elegans to Decipher the Cellular and Molecular Mechanisms Underlying Neurodevelopmental Disorders

Contact Info

Product

Resources

About