Caspase-8 Control Microglia Activation and Neurotoxicity in Parkinson's Disease

Objective/Rationale:
Sustained microglia activation and resulting neuroinflammation is believed to play an important role in the mechanism of chronic dopaminergic neuronal loss in Parkinson’s disease.
We uncovered a completely novel and unexpected role for caspase-8 in the control of microglia activation and associated neurotoxicity to dopaminergic neurons. We aim at providing the genetic evidence that targeting caspase-8 gene selectively in the microglia cell population can provide beneficial effect in pre-clinical models of Parkinson’s disease.

Project Description:
To examine the beneficial effects of deletion of caspase-8 gene in the microglia cell population, we will take advantage of the Cre-lox technologyto generate conditional caspase 8 knockout micein the myeloid lineage, including microglia in the brain. This technology offers us a unique possibility of assessing the involvement of caspase-8 in microglia-mediated brain inflammation and testing its contribution to dopaminergic cell death in pre-clinical models of Parkinson’s disease. Pre-clinical models will be challenged with either lipopolysaccharide intranigrally, a potent direct inducer of microglia activation or with MPTP, which promotes specific nigrostriatal dopaminergic. Parkinson’s disease-relevant features including dopaminergic cell integrity, degree of microglia activationcell type specific and subcellular caspase activation and behavioral tests will be analyzed.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This study will hopefully identify microglial caspase-8 as a therapeutic target for treatment of Parkinson’s disease. Our hypothesis is that silencing caspase-8 gene expression in the microglia cell population will lead to dopaminergic neuronal protection by reducing pro-inflammatory responses in pre-clinical models of Parkinson’s disease. This could lead to the design of novel therapeutic strategies aiming at targeting microglia activation in Parkinson’s patients.

Anticipated Outcome:
We believe this proposal will lead to the identification of microglial caspase-8 as a therapeutic target for Parkinson’s disease. We also anticipate that this study will bring additional information on microglia activation and associated chronic dopaminergic neuronal loss in Parkinson’s disease. Further, this proposal may imply that inhibition of caspase-8 would offer therapeutic potential against microglia-mediated neurotoxicity and dopamine neuron loss.