The project is hot on the trail of key suspect players in Parkinson’s disease. The output of an innovative screening process put forth a handful of candidate enzymes in a lower organism worm based system. These gains will now be channeled into a rodent model of PD, along with another factor called sirtuin1, which could act as a rejuvenator. Key enzyme pathways will be validated for their role in PD which could eventually lead to a new drug.
A previous study identified genes related to pathways involved in PD, from Drs. Kim and Guy Caldwell, University of Alabama, Birmingham. To translate these findings towards a clinical application, this project rationally targets four factors in an animal model closer to humans. In other words, hits from a high throughput screening system in worms will now be applied in a rational manner to rats. The pre-clinical model mimics PD with alpha-synuclein neuropathology and dopamine neuron loss. The chosen factors will be systematically tested in rats to block dopamine neurodegeneration caused by alpha-synuclein. An additional factor of interest will also be tested, sirtuin1, which correlates with enhanced lifespan, to enhance dopamine neuron survival.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project is relevant because it is based on a powerful screening system which targeted a small set of confirmed leads. This study will validate these leads one-by-one in rats, which contain a substantia nigra and striatum dopamine pathway that resembles humans.The PD model in rats, alpha-synuclein overexpression, has advantages over other models. The unique leads and model will hopefully identify an enzyme which could be manipulated by a drug treatment.
High expectations are based on the similarity between the screening model in a lower organism (worms) and the validation model in rats, as both systems use alpha-synuclein overexpression. If the models are relevant to PD, neuroprotective mechanisms may be conserved in evolution, and uncover an important new target for a drug. Bridging consensus mechanisms relevant to PD in various model systems is a goal, although there are a number of possible outcomes.
The aim of the project is target validation, in models that span different stages of evolution. A panel of eleven gene targets that were implicated in high throughput screening models (yeast and worms) as candidate protective factors against Parkinson’s disease (PD), were chosen for analysis. “Hits” that had protective action against alpha?synuclein in a lower organism are tested in rats, which develop PD?like neuropathology and loss of dopaminergic neurons in the substantia nigra when alpha?synuclein is overexpressed. So far, two of the eleven have shown positive signs in terms of preservation of neuron numbers from alpha?synuclein induced loss. One of the targets is a neurotrophic receptor associated protein and the other is a mitochondrial enzyme. Targets that remain consistently protective will be confirmed in another relevant model of PD and compared with parkin co?expression, which is predicted to serve as a positive control and validation of the model as a screen for neuroprotectants. Validation of novel targets derived from a range of pre-clinical models could add to the understanding of the causes of PD, and have therapeutic potential.