Caspase-8 Control Microglia Activation and Neurotoxicity in Parkinson's Disease
Target Validation, 2011
Sustained microglia activation and resulting neuroinflammation is believed to play an important role in the mechanism of chronic dopaminergic neuronal loss in Parkinsonís 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 Parkinsonís disease.
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 Parkinsonís 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. Parkinsonís 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 Parkinsonís Disease:
This study will hopefully identify microglial caspase-8 as a therapeutic target for treatment of Parkinsonís 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 Parkinsonís disease. This could lead to the design of novel therapeutic strategies aiming at targeting microglia activation in Parkinsonís patients.
We believe this proposal will lead to the identification of microglial caspase-8 as a therapeutic target for Parkinsonís disease. We also anticipate that this study will bring additional information on microglia activation and associated chronic dopaminergic neuronal loss in Parkinsonís disease. Further, this proposal may imply that inhibition of caspase-8 would offer therapeutic potential against microglia-mediated neurotoxicity and dopamine neuron loss.
We successfully generated a novel pre-clinical model to investigate the role of microglia activation in Parkinsonís disease, which we hope will be of help for other scientists in the field of Parkinsonís disease research. We validated in vivo that silencing caspase-8 gene expression in the microglia cells reduced their pro-inflammatory responses, which was in turn associated with some beneficial effects for the dopaminergic neurons.
Associate Professor at Karolinska Institutet
Location: Stockholm, Sweden
Professor of Biochemistry at University of Seville
Location: Seville, Spain