Objective/Rationale:
The Sigma-1 receptor (Sig-1R) is a protein involved in the transport of lipids and proteins between organelles within the cell. Impairment of these intracellular trafficking processes is believed to contribute to the demise of dopaminergic neurons and other types of neurons in Parkinson´s disease (PD). This project will evaluate the effects of compounds boosting the activity of Sig-1R in pre-clinical models of PD. We hypothesize that these compounds will have neuroprotective, neurorestorative, and anti-inflammatory properties.
Project Description:
We shall use an intrastriatal 6-OHDA lesion as a pre-clinical model of PD. The study will consist of the following experiments:
Aim 1: We shall compare the neuroprotective and neurorestorative effects of two commercially available Sig-1R receptor agonists and one Sig-1R antagonist. Treatment with these compounds will start on the same day as the 6-OHDA lesion and will continue for either 7 or 35 days.
Aim 2: Here we shall use a “delayed-start” design: the compound or doses found to be effective in the previous experiment will start to be administered at 7 days post-lesion. Treatment will continue for 35 days.
Aim 3: To verify the target specificity of the compounds, we shall apply 6-OHDA lesions and drug treatments to genetically engineered pre-clinical models lacking Sig-1R.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Several mechanisms contribute to the neurodegenerative process in PD, and an ideal disease-modifying therapy should be able to improve more than one mechanism. Based on a vast literature from other disease models, we hypothesize that Sig-1R agonists have the potential to do so. A successful implementation of our project will provide solid support to the idea that Sig-1R should be pursued as a target for disease-modifying therapies in PD.
Anticipated Outcome:
We expect to define at least one Sig-1R treatment regimen that will protect nigral dopamine neurons from 6-OHDA-induced cell death, and/or promote axonal sprouting of their projections to the striatum. We expect these effects to correlate with a reduced activation of microglia in the affected brain regions. Moreover, we hypothesize that Sig-1R knockout pre-clinical models will be resistant to the neuroprotective/neurorestorative effects of Sig-1R agonist treatment.