Objective: Non-dopaminergic protein drug targets are of high interest to develop adjuvant treatments for currently insufficiently addressed symptoms of PD. RGS4, a regulator of G-protein signalling, has recently been proposed as a candidate target. Thus, validation of the neuro-protective effect of RGS4 reduction is an essential next step for exploring the potential of new selective RGS4-inihibiting experimental therapeutics.

Background: To characterize RGS4 in detail and validate it as a putative drug target for PD we have used the 6-OHDA mouse model. This model is widely used and well characterized for the study of movement impairment symptoms in Parkinson’s disease.

Methods: To validate the neuro-protective effect of RGS4 reduction, a cohort of eight mice per genotype (wildtype, partial knockout and complete knockout) and four per gender were generated. At 12 weeks age, two behavioral studies (rear cylinder and grip strength) were performed to evaluate motor function and deficits. Additionally, neuropathological studies were performed using tyrosine hydroxylase immunohistochemistry staining to quantify dopaminergic neuron loss within the substantia nigra region of the midbrain due to the administration of the toxin.

Results: The behavioral study showed that there is no significant difference in the impaired forelimb use as well as grip strength between the RGS4+/+ and RGS4-/- mice at baseline and after 13 days of 2μg 6-OHDA administration. Similarly, the neuropathological study showed that there is no significant difference in dopaminergic neuron loss after partial or complete RGS4 knockout in comparison to the wildtype in the 6-OHDA model.

Conclusions: Both behavioral and neuropathological studies suggest that RGS4 knockout has no neuro-protective effect in comparison to wildtype mice, taking into consideration the variances within each genotype. Specifically, no significant difference was observed in the impaired forelimb use and grip strength between the two RGS4 genotypes at baseline and after 13 days of 2μg 6-OHDA administration. Moreover, a higher extent of dopaminergic neuron loss was observed for RGS4-/- in comparison to the other RGS4 genotypes. These data suggest that targeting RGS4 for neuroprotection in PD should be approached with caution.

« Back to 2016 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-therapeutic-viability-of-a-non-dopaminergic-target-for-parkinsons-disease/