Objective: To study changes of the dopaminergic pathway of a transgene DYT1 dystonia mouse model after induction of a dystonic phenotype by peripheral nerve crush.

Background: 30% of torsinA mutation carriers develop generalized DYT1 dystonia in childhood. Disease onset has been linked to external triggers such as peripheral traumas. The pathophysiology of DYT1 is unclear, the dopaminergic pathway is thought to play a central role. h∆GAG3 mice express the human mutated torsinA, but are asymptomatic in their naïve state. A peripheral nerve crush was used to provoke the development of dystonia-like movements in h∆GAG3 mice and changes of the dopaminergic pathway were studied.

Method: Dystonia-like movements of h∆GAG3 and wildtype (wt) mice were evaluated with a tail suspension test (TST) and a newly developed scoring system from 0-5 points. Electroneurography of the sciatic nerves was performed 10 weeks after crush in order to analyze nerve recovery in h∆GAG3 and wt mice. The striatal dopaminergic system was analysed via HPLC as well as qPCR.

Results: hΔGAG3 mice and their littermate controls developed abnormal hindlimb movements in the first weeks following the sciatic nerve crush. However, hΔGAG3 mice continued to show dystonia-like movements in a significant manner over the observational period of 12 weeks while wt mice recovered almost completely (TST week 12: 2.10 ± 0.30 vs 0.40 ± 0.20, p < 0.0001). The analysis of nerve conduction velocity and compound muscle action potentials 10 weeks after the peripheral trauma showed a similar nerve recovery in h∆GAG3 and wt mice (23.97 m/s ± 1.80 m/s vs 25.30 m/s ± 2.80 m/s). HPLC analysis revealed a slightly elevated dopamine (DA) level in the contralateral striatum of naïve hΔGAG3 mice compared to wt mice (1.15 ± 0.12 vs 1.00 ± 0.06), no significant change was seen after crush. In wt mice the nerve crush led to a significant DA depletion after crush (0.79 ± 0.06) compared to hΔGAG3 mice (1.03 ± 0.18, p < 0.05). DA receptors DRD1-5 did not reveal any significant differences on mRNA level in the contralateral striatum in hΔGAG3 and wt mice after sciatic nerve injury.

Conclusion: A dystonic phenotype was successfully elicited by peripheral nerve injury in this DYT1 mouse model, highlighting the central role of environmental factors in disease pathology. A dopaminergic dysregulation might play a role in a disrupted sensorimotor circuitry.

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/striatal-dopaminergic-dysregulation-and-dystonia-like-movements-induced-by-peripheral-nerve-crush-in-a-transgene-dyt1-mouse-model/