Objective/Rationale:
Alpha-synuclein protein accumulation in the brain causes neurotoxicity in Parkinson’s disease (PD). Neural cells have a protein degradation mechanism called the ubiquitin proteasomal system (UPS) that prevents alpha-synuclein accumulation, but with increasing age it does not function as efficiently. The experimental therapeutic compound, OXD-5, has UPS-stimulating activity, so we will determine if OXD-5 administration can increase alpha-synuclein protein clearance and neuronal survival in a PD model.
Project Description:
A total of 20 pre-clinical Sprague-Dawley models will be prepared by viral infection of mutant alpha-synuclein to the left hemisphere, and a green fluorescence protein control to the right hemisphere. After three weeks to establish alpha-synuclein protein expression, 10 models will be administered OXD-5, and 10 will be administered a vehicle control. Compound administration will be continuous for three weeks. At the beginning and end of treatment, limb motor control will be tested. Upon completion of treatment and motor tests, tissue will be analyzed with chromatography and microscopy.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Ideally, new PD treatments will intervene with pathological mechanisms that drive the course of the disease. Since toxic alpha-synuclein accumulation is a causative factor of PD, administration of OXD-5 to clear alpha-synuclein could have such disease-modifying effects. Since OXD-5 has been used clinically for other indications, its development as a therapeutic for PD could be relatively efficient. As a new therapeutic approach, this project would also open new avenues of PD pre-clinical research.
Anticipated Outcome:
We will determine the capacity of OXD-5 to stimulate the clearance of alpha-synuclein in the brain of a pre-clinical PD model, as well as its capacity to improve dopamine synthesis, neuronal survival, and motor function. It would be the first validation of the compound for PD. The work will help to justify further pre-clinical testing, and will inform the design of follow-up experiments required for its approval as a new PD therapeutic.
Final Outcome
The performed experiments represent the first-ever test of OXD-5 administration to PD models. Postmortem analysis of brain tissue samples showed that administration of OXD-5 drug penetration within the brain was variable. In three cases, OXD-5 brain concentration levels were in the targeted range. A concomitant decrease in alpha-synuclein levels was observed by using quantitative biochemical methods and brain tissue imaging techniques. In the case with the highest brain concentration of OXD-5, there was an approximate five-fold reduction of alpha-synuclein. This case also showed dopamine neurotransmitter and metabolite levels in the normal range. These observations warrant further efforts to optimize OXD-5 delivery methods, and fully validate the hypothesis.