Pharmacological inhibition of acetylcholinesterase improves the locomotion defective phenotype of a SCA3 C. elegans model

Abstract

Inhibition of acetylcholinesterase (AChE) is a common used treatment option for Alzheimer's disease. However, there has been limited research on the potential use of AChE inhibitors for the treatment of Machado-Joseph disease (MJD)/Spinocerebellar Ataxia 3 (SCA3), in spite of the positive results using AChE inhibitors in patients with other inherited ataxias. MJD/SCA3, the most common form of dominant Spinocerebellar Ataxia worldwide, is caused by an expansion of the polyglutamine tract within the ataxin-3 protein, and is characterized by motor impairments. Our study shows that administration of the AChE inhibitor neostigmine is beneficial in treating the locomotion defective phenotype of a SCA3/MJD model of C. elegans and highlights the potential contribution of AChE enzymes to mutant ataxin-3-mediated toxicity.

Figure 1. Pharmacological acetylcholinesterase inhibition ameliorates mutant ATXN3-medited motor defects in a SCA3 C. elegans model

A : neostigmine (0.01-10.0 mM) shows no major toxic effects in C. elegans . Toxicity was assessed using the food clearance assay. The optical density of the OP50 suspension with neostigmne-treated animals ( N2 ) at the concentrations depicted, was measured daily. The mean OD was calculated for each day from five samples and plotted over time. Control DMSO (1%) corresponds to drug vehicle and DMSO at 5% was used as positive (toxic compound) control. B : Locomotion defective behaviour of AT3q130 animals, comparison between treated (neostigmine 0.01-10 mM) and untreated animals in comparison to wild type ( N2 ) and AT3q14 controls. Statistical significant difference determined using One-way ANOVA and Bonferroni’s multiple comparison analysis compared to AT3q130 control: ***p≤0.001 (decreased motility); *p≤0.05, ***p≤0.001; n=5 C : Locomotion defective behaviour of AT3q130 animals, comparison between treated (neostigmine 0.1-10 µM) and untreated animals in comparison to wild type ( N2 ) and AT3q14 controls. Statistical significant difference determined using One-way ANOVA and Bonferroni’s multiple comparison analysis compared to AT3q130 control: ***p≤0.001, **p≤0.01, n=5 D : Locomotion defective behaviour of AT3q130 animals compared to double mutant AT3q130; ace-1 and WT and ace-1 control. Statistical significant difference determined using One-way ANOVA and Bonferroni’s multiple comparison analysis: ***p≤0.001, ns-not significant; n=5 E : Locomotion defective behaviour of AT3q130 animals compared to double mutant AT3q130; ace-2 and WT and ace-2 control. Statistical significant difference determined using One-way ANOVA and Bonferroni’s multiple comparison analysis: *p≤0.05, **p≤0.01, ns-not significant; n=4