رسالة جامعية
Functional roles of adenosine monophosphate-activated protein kinase ?? (AMPK-??) in Huntington's disease
| العنوان: | Functional roles of adenosine monophosphate-activated protein kinase ?? (AMPK-??) in Huntington's disease |
|---|---|
| العنوان البديل: | 腺苷單磷酸活化蛋白激酶在漢丁頓舞蹈症發病過程中之功能角色探討 |
| المؤلفون: | Tz-Chuen Ju, 朱自淳 |
| مرشدي الرسالة: | Yijuang Chern, 陳儀莊 |
| سنة النشر: | 2011 |
| المجموعة: | National Digital Library of Theses and Dissertations in Taiwan |
| الوصف: | 100 Adenosine monophosphate-activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. Herein, we report that activation of the a1 isoform of AMPK (AMPK-α1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt. Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mutant Htt and AMPK overactivation. Moreover, we further demonstrated that mHtt induced oxidative stress which caused activation of the α isoform of AMPK, and subsequent neurodegeneration. Oxidative stress played a critical role in the activation of AMPK revealed by the fact that the level of oxidative stress was higher in striatal cells expressing mutant Htt, and that a blocker of oxidative stress (NAC) suppressed the activation of AMPK. Collectively, our data suggests that activation and nuclear accumulation of AMPK-α1 played a pivotal role in the potentiation of neurodegeneration. These data demonstrate that aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mutant Htt. |
| Original Identifier: | 100YM005291001 |
| نوع الوثيقة: | 學位論文 ; thesis |
| وصف الملف: | 115 |
| الإتاحة: | http://ndltd.ncl.edu.tw/handle/77322584820789446594Test |
| رقم الانضمام: | edsndl.TW.100YM005291001 |
| قاعدة البيانات: | Networked Digital Library of Theses & Dissertations |
| الوصف غير متاح. |