SAGE KE Bulletin Board

Pathology Is Not Necessarily Pathogenic

29 October 2004

Mark A. Smith, George Perry

The recent paper (1) showing that inclusion body formation serves as a protective response to toxic mutant huntingtin should serve as an ominous forewarning to investigators of all neurodegenerative diseases. For decades, inclusion bodies or extracellular aggregations of protein, while serving as the defining pathological hallmarks of many neurodegenerative diseases, have also been stigmatized as being integral to neuronal degeneration and, as such, are much sought after therapeutic targets. However, as found for huntingtin inclusions, pathology is not necessarily pathogenic and Lewy bodies in Parkinson disease or neurofibrillary tangles and senile plaques in Alzheimer disease (AD) likely serve a protective function (2). In this regard, it is notable that oxidative stress in AD is inversely correlated with amyloid-beta load and is reduced by 50% in those neurons that contain inclusions (2). Therefore, it is time to look beyond pathology-based dogma and recognize neurons as biological systems that, in health and disease, are responsive and adaptive. Failure to do so will not only delay our fundamental knowledge of disease processes but could lead us to the wrong therapeutic targets (3).

1. Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., Finkbeiner, S., Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805-810 (2004).

2. Nunomura, A. et al., Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759-767 (2001).

3. Perry, G., Nunomura, A., Raina, A.K., Smith, M.A., Amyloid-beta junkies. Lancet 355, 757 (2000).

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