TY - JOUR
T1 - Impaired antioxydative Keap1/Nrf2 system and the downstream stress protein responses in the motor neuron of ALS model mice
AU - Mimoto, Takafumi
AU - Miyazaki, Kazunori
AU - Morimoto, Nobutoshi
AU - Kurata, Tomoko
AU - Satoh, Kota
AU - Ikeda, Yoshio
AU - Abe, Koji
N1 - Funding Information:
This work was partly supported by Grant-in-Aid for Scientific Research (B) 21390267 and the Ministry of Education, Science, Culture and Sports of Japan , and by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases (Nakano I), and grants (Mizusawa H, Nishizawa M, Sasaki H) from the Ministry of Health, Labour and Welfare of Japan .
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/3/29
Y1 - 2012/3/29
N2 - The Kelch-like ECH-associated protein 1 (Keap1)/Nuclear erythroid 2-related factor 2 (Nrf2) system is the major cellular defense mechanism under oxidative stress, but the role in motor neuron degeneration under amyotrophic lateral sclerosis (ALS) pathology has not yet been fully elucidated. Here we examined temporal and spatial changes of Keap1, Nrf2, and their downstream stress response proteins heme oxgenase-1 (HO-1), glutathione, thioredoxin (TRX), and heat shock protein 70 (HSP70) throughout the course of motor neuron (MN) degeneration in the spinal cord of ALS model mice. Keap1 protein levels progressively decreased in the MN and anterior lumbar cord of ALS mice to 63% at early symptomatic 14 weeks and 58% at end symptomatic 18 weeks, while Nrf2 dramatically increased in the anterior lumbar cord with accumulation in the MN nucleus to 229% at 14 weeks and 471% at 18 weeks when glial like cells became also positive. In contrast, downstream stress response proteins such as HO-1, glutathione, TRX, and HSP70 showed only a small increase in MN with a significant increase to 149% to 280% in the number of glial-like cells after symptomatic 14 weeks. Our present observation suggests that MN selectively lost inductions of these important downstream protective proteins without regard to the Keap1/Nrf2 system activation, which could be a pivotal mechanism of neurodegenerative processes of ALS.
AB - The Kelch-like ECH-associated protein 1 (Keap1)/Nuclear erythroid 2-related factor 2 (Nrf2) system is the major cellular defense mechanism under oxidative stress, but the role in motor neuron degeneration under amyotrophic lateral sclerosis (ALS) pathology has not yet been fully elucidated. Here we examined temporal and spatial changes of Keap1, Nrf2, and their downstream stress response proteins heme oxgenase-1 (HO-1), glutathione, thioredoxin (TRX), and heat shock protein 70 (HSP70) throughout the course of motor neuron (MN) degeneration in the spinal cord of ALS model mice. Keap1 protein levels progressively decreased in the MN and anterior lumbar cord of ALS mice to 63% at early symptomatic 14 weeks and 58% at end symptomatic 18 weeks, while Nrf2 dramatically increased in the anterior lumbar cord with accumulation in the MN nucleus to 229% at 14 weeks and 471% at 18 weeks when glial like cells became also positive. In contrast, downstream stress response proteins such as HO-1, glutathione, TRX, and HSP70 showed only a small increase in MN with a significant increase to 149% to 280% in the number of glial-like cells after symptomatic 14 weeks. Our present observation suggests that MN selectively lost inductions of these important downstream protective proteins without regard to the Keap1/Nrf2 system activation, which could be a pivotal mechanism of neurodegenerative processes of ALS.
KW - ALS
KW - Antioxidant protein
KW - Keap1
KW - Nrf2
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U2 - 10.1016/j.brainres.2011.12.064
DO - 10.1016/j.brainres.2011.12.064
M3 - Article
C2 - 22353756
AN - SCOPUS:84858451400
VL - 1446
SP - 109
EP - 118
JO - Molecular Brain Research
JF - Molecular Brain Research
SN - 0006-8993
ER -