Distribution and cellular localization of high mobility group box protein 1 (HMGB1) in the spinal cord of a transgenic mouse model of ALS

Although the aetiology of amyotrophic lateral sclerosis (ALS) is still elusive, increased attention has been put forward on events related to neuroinflammation and an active participation of glial cells in the ALS pathogenesis has been suggested. However, the specific role of many proinflammatory mediators that usually accompany the inflammatory changes is still largely unknown. High mobility group box protein I (HMGB I) is an ubiquitous nuclear protein that exerts numerous extranuclear and extracellular functions, including a proinflammatory activity, able to induce cytokines expression and activate inflammatory cells. To investigate whether this protein may play a role in the inflammatory events in ALS, we examined both expression and localization of HMGB I in the lumbar spinal cord of SOD I G93A transgenic mice, a well established mouse model of familial ALS, at different stages of the disease. Intense HMGB I reactivity was detected in ventral horn motor neurons of both non-transgenic and SOD I G93A mice and there was no difference in its expression between presymptomatic SOD I G93A mice and controls. With the progression of the disease, degenerating neurons showed a reduction of HMGB I immunoreactivity which could reflect an extracellular release of this protein. By contrast, in the reactive glial cells HMGB I was remarkably expressed in the nucleus, but not in the cytosol, likely contributing to the proliferation and/or hypertrophy of these cells. These results suggest that HMGB I may have a different involvement in the motor neurons and glial cells in response to the neurotoxic environment in the spinal cord of SOD I G93A mice, and it may contribute to the progression of inflammatory and neurodegenerative processes. (c) 2006 Elsevier Ireland Ltd. All rights reserved.