کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8260242 | 1534656 | 2014 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease
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کلمات کلیدی
CaMKKPGC-1αPolyQNLSmHTTpKaCaMKIIN-acetyl-l-cysteine (NAC)VBRHuntington's disease (HD)httThree-dimensionalTAK1nEScAMP-dependent kinaseAICARACCLKB1AMPKAMP-activated protein kinase - AMP-پروتئین کیناز فعال شده استataxia telangiectasia mutated - Ataxia telangiectasia جهش یافته استCa2 +/calmodulin-dependent protein kinase II - Ca2 + / calmodulin وابسته پروتئین کیناز IIamyotrophic lateral sclerosis - اسکلروز جانبی آمیوتروفیکMRI - امآرآی یا تصویرسازی تشدید مغناطیسیAlzheimer's disease - بیماری آلزایمرALS - بیماری اسکلروز جانبی آمیوتروفیکHuntington's disease - بیماری هانتینگتونParkinson's disease - بیماری پارکینسونcompound C - ترکیب CMagnetic resonance imaging - تصویربرداری رزونانس مغناطیسیATM - خودپردازnuclear export signal - سیگنال صادرات هسته ایnuclear localization signal - سیگنال محلی سازی هسته ایwild-type - نوع وحشیHuntingtin - هانتینگتنAMP-activated protein kinase (AMPK) - پروتئین کیناز فعال AMP (AMPK)Polyglutamine - پلیگلوتامینliver kinase B1 - کیناز کیناز B1Reactive oxygen species (ROS) - گونه های اکسیژن واکنشی (ROS)
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Huntington's disease (HD) is an autosomal dominant neurological disorder that is induced by a CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. We previously reported that the abnormal activation of an important energy sensor, AMP-activated protein kinase α1 (AMPK-α1), occurs in the brains of mice and patients with HD, which suggests that this abnormal activation may contribute to neuronal degeneration in HD. In the present study, we demonstrated that the elevated oxidative stress that was evoked by a polyQ-expanded mutant HTT (mHTT) caused the abnormal activation of AMPK-α1 and, subsequently, resulted in neurotoxicity in a striatal progenitor cell line (STHdhQ109) and in the striatum of a transgenic mouse model of HD (R6/2). The systematic administration of an antioxidant (N-acetyl-cysteine, NAC) to R6/2 mice suppressed the activation of AMPK-α1, reduced neuronal toxicity, which was assessed by the activation of caspases, increased neuronal density, ameliorated ventricle enlargement, and improved motor dysfunction. This beneficial effect of NAC in vivo appears to be direct because NAC also reduced the activation of AMPK-α1 and the death of STHdhQ109 cells upon elevated oxidative stress. Moreover, the activation of AMPK enhanced the level of oxidative stress in STHdhQ109 cells, in primary neurons of R6/2 mice, and in the striatum of two different HD mouse models (R6/2 and Hdh150Q/+), whereas the inhibition of AMPK reduced the level of oxidative stress. Collectively, our findings suggest that positive feedback regulation between the elevated oxidative stress and the activation of AMPK-α1 contributes to the progression of HD.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1842, Issue 9, September 2014, Pages 1668-1680
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1842, Issue 9, September 2014, Pages 1668-1680
نویسندگان
Tz-Chuen Ju, Hui-Mei Chen, Yu-Chen Chen, Ching-Pang Chang, Chen Chang, Yijuang Chern,