Somatodendritic accumulation of misfolded SOD1-L126Z in motor neurons mediates degeneration: alphaB-crystallin modulates aggregation.
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) alphaB-crystallin suppressed the in vitro aggregation of SOD1-L126Z. In vivo, alphaB-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.
Departement of Pathology, The John's Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jiou
J
Wang
Guilian
G
Xu
Hong
H
Li
Victoria
V
Gonzales
David
D
Fromholt
Celeste
C
Karch
Neal G
NG
Copeland
Nancy A
NA
Jenkins
David R
DR
Borchelt
D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000648:ultrastructure; D003712:Dendrites / Q000201:enzymology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000648:ultrastructure; D017510:Protein Folding; D017384:Sequence Deletion; D013116:Spinal Cord / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation; D038203:alpha-Crystallin B Chain / Q000378:metabolism*
C000606290:SOD1 protein, human; D038203:alpha-Crystallin B Chain; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1