Neurodegenerative diseases are diseases that cause progressive degeneration and death of nerve cells. Neurodenegerative disorders include diseases with high impacts on human health and high costs to society, including Alzheimer’s Disease, Amyotrophic lateral sclerosis (ALS), and Parkinson’s Disease. Neurodegenerative diseases are often age-related, with significant pathological and clinical similarities to each other. For humans, these disease are often progressive and incurable.
A major goal of neurodegeneration research is therefore to identify potential new therapeutic compounds that can slow or even reverse disease progression, either by impacting directly on the neurodegenerative process or by activating endogenous physiological neuroprotective mechanisms that decline with aging .
Though mammalian models are very powerful, they are prohibitively expensive for high-throughput drug screens. Given the highly conserved neurological pathways between mammals and invertebrates, C. elegans has emerged as a powerful tool for neuroprotective compound screening. The information below illustrate how C. elegans has been used to model various human aging-associated neurodegenerative diseases and provide an extensive list of compounds that have therapeutic activity in these worm models and so may have translational potential .
The effects of the neurotransmitter, serotonin are shown. The worm on the right has a higher pumping rate (compared to the control worm at left) due to an excess of endogenous serotonin.
The ScreenChip phenotyping platform makes it possible to get real-time, quantitative behavioral readouts of nervous system function without the need for tedious sample preparation, high-speed cameras or post-hoc measurements. By gaining access to quantitative data characterizing the neuromuscular function of the pharyngeal organ, you can:
- Uncover novel mechanisms and pathways involved in neurodegenerative diseases
- Reduce experimental time and variability through rapid automatic data acquisition
- Get quantitative data from your worms to identify novel disease mechanisms
- Measure the effects of drugs and compounds rapidly
- Gain access to muscular responses to synaptic events in a fully described and well-characterized nervous system
Key advantages of the ScreenChip System phenotyping assay:
- Visualize and quantify neuromuscular function with large populations (Fig. 1)
- Rapidly measure and compare the effects of clinically relevant mutations and potential drug leads on live animals (Fig. 2)
- Measure phenotypic readouts of genetic and pharmacological manipulations by monitoring of fluorescent probes, morphological changes, and behavioral responses such as pharyngeal pumping (Fig. 3)
- Measure and compare the effects of clinically relevant mutations and ‘humanized’ worms (with disease-relevant genes) (Fig. 4)
- Access novel phenotypes to uncover neuronal mechanisms (Fig. 5)
Visualize and quantify neuromuscular function with large populations
Fig. 1: Serotonin (5HT) is a neurotransmitter with widespread regulatory effects in humans, from depression to neurodegeneration. Recent data obtained with the ScreenChip platform allowed us to model the serotonin biochemical pathway using a sensitive measure for pharyngeal pumping in C. elegans. 47 to 92 worms per condition were tested to obtain this data.
Rapidly measure and compare the effects of clinically relevant mutations and potential drug leads on live animals
Fig. 2: Visualization of the feeding behavior of two worms. The CL4176 Alzheimer’s disease model overexpresses the human A-beta protein in the worms’ body-wall muscle but not in the pharynx. The ScreenChip system lets you visualize the modified pattern of feeding of this Alzheimer’s disease model. The pump frequency is similar between control (CL802) and Alzheimer’s disease worms, but the ScreenChip data allowed us to uncover the drastically impaired pattern of pumping.
Measure phenotypic readouts of genetic and pharmacological manipulations by monitoring of fluorescent probes, morphological changes, and behavioral responses such as pharyngeal pumping
Fig. 3: (Bottom) Adult C. elegans worm within the ScreenChip expressed fluorescent markers GC6 in the body-wall muscles (green) and TdTomato in the 6th layer of the pharyngeal muscle (red). (Top) GFP expression controlled by odr-2 promoter in a C. elegans L4 larva within the ScreenChip platform.
Measure and compare the effects of clinically relevant mutations and ‘humanized’ worms (with disease-relevant genes)
Fig. 4: Effect of serotonin reuptake transporter gain-of-function in ‘humanized’ worms (SLC6A4, created by Knudra). SLC6A4, the human homologue of serotonin reuptake transporter mod-5, was inserted to be strongly expressed in the pharynx, thus restoring pharyngeal pumping in mod-5 mutants to levels comparable to control (N2).
Learn more about RediMODEL Kits from Knudra Transgenics.
Gain access to muscular responses to synaptic events in a fully described and well-characterized nervous system
Fig. 5: (Left) Hassan et al, 2009: Aβ42 or GFP were expressed at low levels at 16°C, while moving the animals to 25°C induced high levels of transgene expression. GFP fluorescence was detected in the pharynx at 16 and at 25°C (narrow black arrows), which is consistent with constitutive pharyngeal expression. In body wall muscle, however, GFP fluorescence was only detectable at 25°C (wide white arrows). (Right) Visualization and quantification of interpump intervals in adult worms. Data from 2 populations of young adults were compiled to visualize the gradual lengthening of the duration of one pumping motion of the pharynx.
-  Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases