Expression of N19S-SOD1, an SOD1 mutant found in sporadic amyotrophic lateral sclerosis patients, induces low-grade motoneuronal toxicity.
Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease. It has been generally accepted that the proapoptotic property of the familial ALS (FALS)-linked mutant SOD1 genes plays an important role in the pathogenesis of some FALS cases. We found here that expression of N19S-SOD1, a novel SOD1 mutant originally found in a sporadic ALS patient, induces lower grade death in NSC34 cells than FALS-linked mutant SOD1. In agreement, intracytoplasmic aggregate formation and SOD1 polymerization are less prominently induced by ectopic expression of N19S-SOD1 than FALS-linked mutant SOD1. We further found that additional cell stresses, such as inhibition of proteasomal activity or up-regulation of intracellular oxidative stress, enhance N19S-SOD1-induced aggregate formation and polymerization of N19S-SOD1. Such analysis of the intracellular polymerization and the ubiquitination of N19S-SOD1 have further suggested that it is recognized as a misfolded protein, like FALS-linked mutant SOD1, whereas wild-type SOD1 is not. Altogether, it is speculated that the N19S mutation of SOD1 in cooperation with associated cell stresses contributes to the onset of ALS as a risk factor.
Obata
Yuji
Y
Department of Pharmacology and Neurosciences, KEIO University School of Medicine,Shinjuku-ku, Tokyo, Japan.
Niikura
Takako
T
Kanekura
Kohsuke
K
Hashimoto
Yuichi
Y
Kawasumi
Masaoki
M
Kita
Yoshiko
Y
Aiso
Sadakazu
S
Matsuoka
Masaaki
M
Nishimoto
Ikuo
I
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016466:CHO Cells; D016923:Cell Death / Q000502:physiology; D006224:Cricetinae; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014162:Transfection
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1