TY - JOUR
T1 - High molecular weight complexes of mutant superoxide dismutase 1
T2 - Age-dependent and tissue-specific accumulation
AU - Wang, Jiou
AU - Xu, Guilian
AU - Borchelt, David R.
N1 - Funding Information:
The authors thank Dr. Jamuna Subramaniam for her assistance in generating the transgenic mice needed for this study and for advice on the detection of CCS. We also thank Dr. Don Cleveland for providing the G85R-Line 164 and G37R-Line 42 mice, and Dr. Philip Wong for providing the G37R-Line 29 mice. We also thank Drs. Jeffery Rothstein (CCS antibody) and Peter Davies (Tau antibody) for their kind gifts of antibody. This work was supported by grants from the NIH (R01 NS 37225; R01 NS 37145), the ALS Association, and the JHU Center for ALS Research.
PY - 2002/3
Y1 - 2002/3
N2 - Mutations in the cytosolic enzyme, superoxide dismutase 1, have been identified as the cause of motor neuron disease in a subset of cases of familial amyotrophic lateral sclerosis. It has been postulated that the injurious property of mutant enzyme resides in its propensity to aggregate or its propensity to catalyze deleterious, copper-mediated, chemistries. Aggregates of SOD1 have been identified, histologically, in neurons and astroglia of the spinal cords of SOD1-linked FALS patients and in transgenic mice that express these mutant proteins. In the present study, we have employed a technique used in detecting and quantifying aggregates of mutant huntingtin (cellulose acetate filtration) to examine the molecular characteristics of mutant SOD1 in three previously characterized transgenic mouse models of FALS. We show that the brains and spinal cords of these mice accumulate mutant SOD1 complexes that can be trapped by cellulose acetate filtration. The relative abundance of these structures increases dramatically with age. Although expressed to the same level in nonnervous tissues, mutant SOD1 was not found in high molecular weight structures. We conclude that some aspect of the biology of neural tissues (in a setting of declining motor neuron function) predisposes to the accumulation of high molecular weight complexes of mutant SOD1.
AB - Mutations in the cytosolic enzyme, superoxide dismutase 1, have been identified as the cause of motor neuron disease in a subset of cases of familial amyotrophic lateral sclerosis. It has been postulated that the injurious property of mutant enzyme resides in its propensity to aggregate or its propensity to catalyze deleterious, copper-mediated, chemistries. Aggregates of SOD1 have been identified, histologically, in neurons and astroglia of the spinal cords of SOD1-linked FALS patients and in transgenic mice that express these mutant proteins. In the present study, we have employed a technique used in detecting and quantifying aggregates of mutant huntingtin (cellulose acetate filtration) to examine the molecular characteristics of mutant SOD1 in three previously characterized transgenic mouse models of FALS. We show that the brains and spinal cords of these mice accumulate mutant SOD1 complexes that can be trapped by cellulose acetate filtration. The relative abundance of these structures increases dramatically with age. Although expressed to the same level in nonnervous tissues, mutant SOD1 was not found in high molecular weight structures. We conclude that some aspect of the biology of neural tissues (in a setting of declining motor neuron function) predisposes to the accumulation of high molecular weight complexes of mutant SOD1.
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U2 - 10.1006/nbdi.2001.0471
DO - 10.1006/nbdi.2001.0471
M3 - Article
C2 - 11895367
AN - SCOPUS:0036199623
SN - 0969-9961
VL - 9
SP - 139
EP - 148
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 2
ER -