Mutant SOD1 linked to familial amyotrophic lateral sclerosis, but not wild-type SOD1, induces ER stress in COS7 cells and transgenic mice.
Mutations in a Cu, Zn-superoxide dismutase (SOD1) cause motor neuron death in human familial amyotrophic lateral sclerosis (FALS) and its mouse model, suggesting that mutant SOD1 has a toxic effect on motor neurons. However, the question of how the toxic function is gained has not been answered. Here, we report that the mutant SOD1s linked to FALS, but not wild-type SOD1, aggregated in association with the endoplasmic reticulum (ER) and induced ER stress in the cDNA-transfected COS7 cells. These cells showed an aberrant intracellular localization of mitochondria and microtubules, which might lead to a functional disturbance of the cells. Motor neurons of the spinal cord in transgenic mice with a FALS-linked mutant SOD1 also showed a marked increase of GRP78/BiP, an ER-resident chaperone, just before the onset of motor symptoms. These data suggest that ER stress is involved in the pathogenesis of FALS with an SOD1 mutation.
Tobisawa
Shinsuke
S
Third Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Hozumi
Yasukazu
Y
Arawaka
Shigeki
S
Koyama
Shingo
S
Wada
Manabu
M
Nagai
Makiko
M
Aoki
Masashi
M
Itoyama
Yasuto
Y
Goto
Kaoru
K
Kato
Takeo
T
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009046:Motor Neurons / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D012313:RNA / Q000097:blood / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013314:Stress, Mechanical; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014162:Transfection
D017931:DNA Primers; D018076:DNA, Complementary; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D012313:RNA; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1