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New phenotype discovered for NPC disease using C. elegans

Effects of Cholesterol on New NPC Disease Phenotype

We discovered that in the absence of cholesterol, NPC mutants display a lower pharyngeal pumping frequency and a longer duration between pumps than control N2 animals (see Figure 1).

Collaborative C. elegans Research Progress on Nieman-Pick Type C

This is the progress we made in our collaborative research project with Perlara and investigation into the lysosomal disorder, Niemann-Pick Type C (NPC). Previous to this work, known phenotypes for C. elegans NPC models (ncr-1 mutants1) included slowed growth, small brood sizes, tendency to enter the dormant (called dauer) stage and a higher incidence of mortality in larval stages. It was also known that these NPC models display sensitivity to a lack of cholesterol2. Our new data supports this and adds this new phenotype.

Fig-A-500x335.png Fig-B-500x304.png

Pharyngeal Pumping Analysis in C. elegans NPC Models

Figure 1.  We measured pharyngeal pumping in first day adult ncr-1 mutants (C. elegans NPC disease models) and control N2 worms in the presence and absence of cholesterol.  A) We observed a significant reduction in mean pumping frequency for ncr-1 mutants deprived of cholesterol (***p < 0.0001); no difference was observed for N2 worms with and without cholesterol.  B) A cumulative distribution plot of inter-pumping interval reveals that ncr-1 mutants without cholesterol also displayed longer duration between pumps; median values (indicated with horizontal grey line) for N2 and ncr-1 -cholesterol are significantly different (p < 0.05). Data from four experimental days are pooled and samples sizes are as follows: n= 32 (N2 +chol), 52 (N2 -chol), 55 (ncr-1 +chol), 46 (ncr-1 -chol).

Since nematodes need cholesterol but do not produce it (like we do), they usually acquire it from their food: decomposing plant material3. Since we do not provide them with decaying leaves, we grow worms on agar plates that contain a small amount of cholesterol. In this experiment, we measured pharyngeal pumping in worms grown (from L1 to first-day adult) on plates with cholesterol as well as plates made without the addition of cholesterol.

The lack of cholesterol affects pharyngeal pumping in ncr-1 mutants. Pumping in these worms is significantly different than all other treatments (i.e., N2s grown +/- cholesterol and ncr-1 mutants + cholesterol). With this phenotype established, we can move forward to test potential drug treatments for NPC.

One more thing: the EPGs themselves also look strange in these ncr-1 mutants – but we’ll post more about that later!

1) Sym et al., 2000
2) Li et al., 2004
3) Frezal and Felix 2015

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