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Human Molecular Genetics Advance Access originally published online on July 6, 2005
Human Molecular Genetics 2005 14(16):2335-2347; doi:10.1093/hmg/ddi236
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Somatodendritic accumulation of misfolded SOD1-L126Z in motor neurons mediates degeneration: {alpha}B-crystallin modulates aggregation

Jiou Wang1,2, Guilian Xu1, Hong Li1, Victoria Gonzales1, David Fromholt1, Celeste Karch1, Neal G. Copeland3, Nancy A. Jenkins3 and David R. Borchelt1,2,*

1Department of Pathology and 2Department of Neuroscience, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Room 558, Baltimore, MD 21205, USA and 3Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA

* To whom correspondence should be addressed at: Department of Neuroscience, College of Medicine, McKnight Brain Institute of the University of Florida, University of Florida, 100 Newell Drive, Room L1-100H, PO Box 100244, Gainesville, FL 32610-0244, USA. Tel: +1 3522940105; Fax: +1 3523928347; Email: borchelt{at}mbi.ufl.edu

Received April 6, 2005; Revised June 16, 2005; Accepted June 28, 2005

Mice expressing variants of superoxide dismutase-1 (SOD1) encoding C-terminal truncation mutations linked to familial amyotrophic lateral sclerosis (FALS) have begun to define the role of misfolding and aggregation in the pathogenesis of disease. Here, we examine transgenic mice expressing SOD1-L126Z (Z=stop-truncation of last 28 amino acids), finding that detergent-insoluble mutant protein specifically accumulates in somatodendritic compartments. Soluble forms of the SOD1-L126Z were virtually undetectable in spinal cord at any age and the levels of accumulated protein directly correlated with disease symptoms. Neither soluble nor insoluble forms of SOD1-L126Z were transported to distal axons. In vitro, small heat shock protein (Hsp) {alpha}B-crystallin suppressed the in vitro aggregation of SOD1-L126Z. In vivo, {alpha}B-crystallin immunoreactivity was most abundant in oligodendrocytes and up-regulated in astrocytes of symptomatic mice; neither of these cell-types accumulated mutant SOD1 immunoreactivity. These results suggest that damage to motor neuron cell bodies and dendrites within the spinal cord can be sufficient to induce motor neuron disease and that the activities of chaperones may modulate the cellular specificity of mutant SOD1 accumulation.


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