Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 198, Issue 11, Pages 1729-1740Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20030975
Keywords
multiple sclerosis; glia; neurodegeneration; encephalomyelitis; integrins
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Funding
- NIMH NIH HHS [R24 MH059724] Funding Source: Medline
- NINDS NIH HHS [R01 NS008952, NS 11920, NS 08952, P50 NS011920] Funding Source: Medline
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Multiple sclerosis (MS) is a chronic demyelinating disease in which it has only recently been suggested that damage to neuronal structures plays a key role. Here, we uncovered a link between the release of lipid breakdown products, found in the brain and cerebrospinal fluid (CSF) of MS patients as well as in experimental autoimmune encephalomyelitis, and neuronal damage mediated by microglial activation. The concentrations of the breakdown product 7-ketocholesterol detected in the CSF of MS patients were capable of inducing neuronal damage via the activation and migration of microglial cells in living brain tissue. 7-ketocholesterol rapidly entered the nucleus and activated poly (ADP-ribose)-polymerase (PARP)-1, followed by the expression of migration-regulating integrins CD11a and intercellular adhesion molecule 1. These findings reveal a novel mechanism linking demyelination and progressive neuronal damage, which might represent an underlying insidious process driving disease beyond a primary white matter phenomenon and rendering the microglial PARP-1 a possible antiinflammatory therapeutic target.
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