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Fig. 2 | Molecular Neurodegeneration

Fig. 2

From: Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans

Fig. 2

Coiling results from early dopaminergic neuron dysfunction due to α-synuclein preceding neuronal loss. (a) Left: Loss of dopaminergic ADE neurons over time for C. elegans expressing A30P α-synuclein plus GFP in dopaminergic neurons (N = 3 populations of n = 50 animals) and for C. elegans expressing GFP alone (N = 4 populations of n = 50 animals) (two-way ANOVA with Bonferroni’s post-hoc test, **p < 0.01, ***p < 0.001, ****p < 0.0001 comparing syn plus GFP and GFP alone animals on the same experimental day). Each data point represents an individual population. Right: Representative fluorescent microscopy images of surviving ADE dopaminergic neurons (arrowheads). (b) CRE-GFP reporter in SIA cholinergic neurons is used to assess for intact (GFP expression “OFF”) or disrupted (GFP expression “ON”) presynaptic signalling from the upstream CEP dopaminergic neuron. (c) Top: Representative fluorescent microscopy images of GFP positive SIA cholinergic neurons (arrowheads). Bottom: Quantification of number of GFP positive SIA neurons (left graph) and percentage of animals with GFP positive SIA neurons (right graph) for control animals not expressing α-synuclein (No syn) (N = 104 animals), syn animals (N = 100 animals), and a tyrosine hydroxylase mutant strain cat-2 (e1112) (N = 104 animals) (one-way ANOVA with Tukey’s post-hoc test, ****p < 0.0001). (d) Left: Coiler scores of syn animals treated with increasing concentrations of exogenous dopamine, normalized to vehicle treated control GFP animals (N = 3 populations of n = 10 animals per treatment condition) (one-way ANOVA with Dunnett’s post-hoc test, *p < 0.05, **p < 0.01 relative to [Dopamine] 0 mM). Right: Coiler scores of control GFP animals treated with 1 mM raclopride (N = 16 populations of n = 10 animals) or vehicle (N = 12 populations of n = 10 animals), normalized to vehicle treated control GFP animals (two-tailed t-test, **p < 0.01). Each data point represents an individual population. (e) Gene ontology enrichment analysis of biological processes implicated in coiling using 97 genes from C. elegans strains previously reported to demonstrate coiling behaviour. Biological processes over-represented by a factor of > 100 were ranked according to the –log10 false discovery rate

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