Journal Article

Somatodendritic accumulation of misfolded SOD1-L126Z in motor neurons mediates degeneration: αB-crystallin modulates aggregation

Jiou Wang, Guilian Xu, Hong Li, Victoria Gonzales, David Fromholt, Celeste Karch, Neal G. Copeland, Nancy A. Jenkins and David R. Borchelt

in Human Molecular Genetics

Volume 14, issue 16, pages 2335-2347
Published in print August 2005 | ISSN: 0964-6906
Published online July 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi236
Somatodendritic accumulation of misfolded SOD1-L126Z in motor neurons mediates degeneration: αB-crystallin modulates aggregation

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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) αB-crystallin suppressed the in vitro aggregation of SOD1-L126Z. In vivo, αB-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.

Journal Article.  8816 words.  Illustrated.

Subjects: Genetics and Genomics

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