Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells
| Autor: | Francis J. Castellino, Anna B. Zlokovic, Berislav V. Zlokovic, Don W. Cleveland, Rashid Deane, Nicole Paquette, Todd Liu, Nienwen Chow, Meenakshisundaram Thiyagarajan, Zhihui Zhong, Hristelina Ilieva, Lee Hallagan, Robert D. Bell, José A. Fernández, Itender Singh, John H. Griffin, Steven M. Lane, Konstantin Stojanovic |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Endothelium Sp1 Transcription Factor Receptors Proteinase-Activated SOD1 Receptors Cell Surface Biology Blood–brain barrier Gene Expression Regulation Enzymologic Cell Line Mice Fibrinolytic Agents medicine Animals Cells Cultured Cell Nucleus Motor Neurons Endothelial protein C receptor Sp1 transcription factor Microglia Superoxide Dismutase Amyotrophic Lateral Sclerosis General Medicine Disease Models Animal Neuroprotective Agents medicine.anatomical_structure Spinal Cord nervous system Blood-Brain Barrier Cell culture Immunology Cancer research Protein C Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci38476 |
| Popis: | Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood-spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood-spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor-1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APC-mediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS. |
| Databáze: | OpenAIRE |
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