Reactive microgliosis: extracellular μ-calpain and microglia-mediated dopaminergic neurotoxicity
Open Access
- 29 January 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 133 (3), 808-821
- https://doi.org/10.1093/brain/awp333
Abstract
Microglia, the innate immune cells in the brain, can become chronically activated in response to dopaminergic neuron death, fuelling a self-renewing cycle of microglial activation followed by further neuron damage (reactive microgliosis), which is implicated in the progressive nature of Parkinson’s disease. Here, we use an in vitro approach to separate neuron injury factors from the cellular actors of reactive microgliosis and discover molecular signals responsible for chronic and toxic microglial activation. Upon injury with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium, N27 cells (dopaminergic neuron cell line) released soluble neuron injury factors that activated microglia and were selectively toxic to dopaminergic neurons in mixed mesencephalic neuron-glia cultures through nicotinamide adenine dinucleotide phosphate oxidase. μ-Calpain was identified as a key signal released from damaged neurons, causing selective dopaminergic neuron death through activation of microglial nicotinamide adenine dinucleotide phosphate oxidase and superoxide production. These findings suggest that dopaminergic neurons may be inherently susceptible to the pro-inflammatory effects of neuron damage, i.e. reactive microgliosis, providing much needed insight into the chronic nature of Parkinson’s disease.Keywords
This publication has 51 references indexed in Scilit:
- 1-Methyl-4-phenylpyridinium-induced alterations of glutathione status in immortalized rat dopaminergic neuronsToxicology and Applied Pharmacology, 2007
- Reactive microgliosis participates in MPP+‐induced dopaminergic neurodegeneration: role of 67 kDa laminin receptorThe FASEB Journal, 2006
- Calpains and DiseaseNew England Journal of Medicine, 2005
- Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanismProgress in Neurobiology, 2005
- Matrix Metalloproteinase-3: A Novel Signaling Proteinase from Apoptotic Neuronal Cells That Activates MicrogliaJournal of Neuroscience, 2005
- Age‐dependent myelin degeneration and proteolysis of oligodendrocyte proteins is associated with the activation of calpain‐1 in the rhesus monkeyJournal of Neurochemistry, 2002
- Matrix Vesicles and Media Vesicles as Nonclassical Pathways for the Secretion of m-Calpain from MC3T3-E1 CellsBiochemical and Biophysical Research Communications, 2001
- Calpain activity and expression increased in activated glial and inflammatory cells in penumbra of spinal cord injury lesionJournal of Neuroscience Research, 2000
- Reactive microgliosisProgress in Neurobiology, 1999
- Chronic Parkinsonism in Humans Due to a Product of Meperidine-Analog SynthesisScience, 1983