Modeling neurodegenerative diseases in Caenorhabditis elegans

doi:10.1016/j.expneurol.2013.09.024

Experimental Neurology

Volume 250, December 2013, Pages 94-103

https://doi.org/10.1016/j.expneurol.2013.09.024 Get rights and content

Abstract

Neurodegenerative diseases which include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and others are becoming an increasing threat to human health worldwide. The degeneration and death of certain specific groups of neurons are the hallmarks of these diseases. Despite the research progress in identification of several disease-related genes, the mechanisms underlying the neurodegeneration in these diseases remain unclear. Given the molecular conservation in neuronal signaling between Caenorhabditis elegans and vertebrates, an increasing number of research scientists have used the nematode to study this group of diseases. This review paper will focus on the model system that has been established in C. elegans to investigate the pathogenetic roles of those reported disease-related genes in AD, PD, ALS, HD and others. The progress in C. elegans provides useful information of the genetic interactions and molecular pathways that are critical in the disease process, and may help better our understanding of the disease mechanisms and search for new therapeutics for these devastating diseases.

Introduction

Neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and others result from the neurodegenerative processes. As the average of human longevity increases, neurodegenerative diseases become more prevalent and have greater social and economic impact worldwide. All of these neurodegenerative diseases have a common pathological feature of aggregated protein accumulation either extracellularly or within the affected neurons, but the detailed mechanisms underlying neurodegeneration remain unknown. And so far there is no effective therapy to cure or stop the progression of those diseases. Recently, several genetic and environmental factors that cause those neurodegenerative diseases have been identified. Understanding how these factors affect neurons is critical for the treatment of these diseases. Due to the complexity of these diseases, many model organism systems have been established to attempt to identify the mechanisms of disease process. The models of organism systems include primate model (Macaca mulatta), rodent model (Rattus norvegicus and Mus musculus), fish model (Danio rerio), fly model (Drosophila melanogaster), yeast model (Saccharomyces cerevisiae), and worm model (Caenorhabditis elegans). In this review paper, we update the new development of generation and application of C. elegans) model for the study of neurodegenerative diseases.

C. elegans is a small nematode with a life cycle of 3.5 days and a lifespan of about 3 weeks at 20 °C. The nervous system of C. elegans is composed of 302 neurons, which utilize most of the known neurotransmitters in the mammalian nervous system, including γ-aminobutyric acid (GABA), dopamine, glutamate, serotonin, and acetylcholine. It has been estimated that about 42% of the human disease genes have an ortholog in the genome of C. elegans (Markaki and Tavernarakis, 2010). In addition, genetic manipulations (forward genetic screen, reverse genetic RNAi screens, rapid mutation mapping, and transgenic worm generation) can be easily performed and fluorescence labeled specific neurons can be visualized in vivo, which make the C. elegans an excellent model to study neurodegenerative diseases. C. elegans has been utilized in modeling various neurodegenerative diseases, including Aβ-associated AD, α-synuclein-linked PD, SOD1-linked ALS and polyQ-related HD. In this paper, we review the current development and application of C. elegans models in the four neurodegenerative diseases, and highlight the recent discoveries of the pathogenesis underlying these diseases and novel therapeutic strategies tested on the C. elegans models to target specific neurodegenerative diseases (Fig. 1).

Section snippets

Alzheimer's disease (AD)

AD is the most common form of dementia that results in the degeneration of neurons and synapses in the cerebral cortex and certain subcortical regions. It is characterized by the formation of amyloid plaques and neurofibrillary tangles in the brains of the AD patients (Huang and Mucke, 2012). The major components of amyloid plaques are β-amyloid (Aβ) peptide and the neurofibrillary tangles that mainly contain hyperphosphorylated tau protein. Aβ is a small peptide with 40 to 42 amino acids, and

Parkinson's disease (PD)

PD is the second most common neurodegenerative disease characterized by the progressive loss of dopamine neurons in the substantia nigra compacta, which results in involuntary movements including bradykinesia, resting tremors, and difficulty in balance and muscle rigidity. One of the pathological hallmarks of PD is the formation of Lewy bodies, which are mainly composed of α-synuclein, neurofilament, and ubiquitin (Hardy, 2010). Approximately 5%–10% of PD is familial case (Wood-Kaczmar et al.,

Amyotrophic lateral sclerosis (ALS)

ALS, which is a devastating, adult-onset, and fatal paralytic disorder, is characterized by dysfunction and degeneration of motor neurons in brain and spinal cord. Approximately 10% of the ALS cases are familial ALS (FALS) and about 20% of FALS are associated with mutations in the Cu/Zn superoxide dismutase 1 gene (SOD1) (Chen et al., 2013, Robberecht and Philips, 2013). Recently, mutations in TAR DNA-binding protein-43 (TDP-43), fused sarcoma (FUS), ubiquilin 2, profiling 1 and others have

Huntington's disease (HD)

HD is an autosomal-dominant neurodegenerative disorder caused by a CAG triplet expansion in the N-terminal of the huntingtin protein (Huntington's Disease Collaborative Research Group, 1993). The pathogenic protein with abnormally expanded track of glutamines (PolyQ) becomes misfolded and aggregated, leading to neural dysfunction (DiFiglia et al., 1997).

The first HD C. elegans model was established by expressing a huntingtin fragment with a 150 repeat polyglutamine (Htt-Q150) in sensory neurons

Conclusions

Several human genes associated with neurodegenerative diseases have been identified. But it is still unclear why only specific neurons are affected. The mechanism that contributes to neuron degeneration remains to be elucidated. Analyzing the diseases-related genes in the model organisms will be a great help to understand the disease process. Although the C. elegans models might not exactly mimic the pathophysiology of human neurodegenerative diseases, the small and transparent nematode has

Conflict of interest

The authors have declared no conflict of interest.

Acknowledgments

This work was supported by grants from the National Basic Research Program of China (No. 2011CB510003) and the National Natural Sciences Foundation of China (No. 81171201 and 81370470).

Conflict of interest

The authors have declared no conflict of interest.

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ReviewModeling neurodegenerative diseases in Caenorhabditis elegans

Abstract

Introduction

Section snippets

Alzheimer's disease (AD)

Parkinson's disease (PD)

Amyotrophic lateral sclerosis (ALS)

Huntington's disease (HD)

Conclusions

Conflict of interest

Acknowledgments

Neuron

Neurobiol. Aging

Molecular Neurodegeration.

Neurobiol. Dis.

J. Biol. Chem.

Neuron

Cell

J. Biol. Chem.

Neurobiol. Aging

Biol. Psychiatry

Neurobiol. Dis.

Neuron

Neurobiol. Dis.

J. Biol. Chem.

J. Biol. Chem.

Neurotoxicology

Neurobiol. Dis.

J. Biol. Chem.

Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan

Nature

Neurotoxic effects of TDP-43 overexpression in C. elegans

Hum. Mol. Genet.

Daf-2 signaling modifies mutant SOD1 toxicity in C. elegans

PLoS One

Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson's disease

J. Mol. Med. (Berl.)

Early-onset Parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes

Neurology

Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model

J. Neurosci.

Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans

J. Neurosci.

Opposing activities protect against age-onset proteotoxicity

Science

Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models

Science

A role for Caenorhabditis elegans in understanding the function and interactions of human disease genes

Hum. Mol. Genet.

apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor

Proc. Natl. Acad. Sci. U. S. A.

Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia

Nature

Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species

J. Neurosci.

Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain

Science

Genetic mechanisms of coffee extract protection in a Caenorhabditis elegans model of beta-amyloid peptide toxicity

Genetics

Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron

Proc. Natl. Acad. Sci. U. S. A.

Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity

Proc. Natl. Acad. Sci. U. S. A.

Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity

Hum. Mol. Genet.

In vivo aggregation of beta-amyloid peptide variants

J. Neurochem.

Interaction of intracellular beta amyloid peptide with chaperone proteins

Proc. Natl. Acad. Sci. U. S. A.

Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain

J. Neurosci.

Progressive disruption of cellular protein folding in models of polyglutamine diseases

Science

Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity

PLoS Genet.

Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity

Nat. Genet.

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group

Cell

MSUT2 is a determinant of susceptibility to tau neurotoxicity

Review
Modeling neurodegenerative diseases in Caenorhabditis elegans