Gedunin Degrades Aggregates of Mutant Huntingtin Protein and Intranuclear Inclusions via the Proteasomal Pathway in Neurons and Fibroblasts from Patients with Huntington's Disease.
10.1007/s12264-019-00421-5
- Author:
Weiqi YANG
1
;
Jingmo XIE
2
;
Qiang QIANG
3
;
Li LI
4
;
Xiang LIN
5
;
Yiqing REN
3
;
Wenlei REN
3
;
Qiong LIU
1
;
Guomin ZHOU
1
;
Wenshi WEI
3
;
Hexige SAIYIN
6
;
Lixiang MA
7
Author Information
1. Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
2. Department of Anatomy, Histology and Embryology, Zhaoqing Medical College, Zhaoqing, 526000, China.
3. Department of Neurology, Huadong Hospital, Fudan University, Shanghai, 200040, China.
4. Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
5. Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
6. School of Life Sciences, Fudan University, Shanghai, 200438, China. saiyin@fudan.edu.cn.
7. Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. lxma@fudan.edu.cn.
- Publication Type:Journal Article
- Keywords:
Degradation;
Gedunin;
Huntington’s disease;
Mutant Huntingtin protein
- From:
Neuroscience Bulletin
2019;35(6):1024-1034
- CountryChina
- Language:English
-
Abstract:
Huntington's disease (HD) is a deadly neurodegenerative disease with abnormal expansion of CAG repeats in the huntingtin gene. Mutant Huntingtin protein (mHTT) forms abnormal aggregates and intranuclear inclusions in specific neurons, resulting in cell death. Here, we tested the ability of a natural heat-shock protein 90 inhibitor, Gedunin, to degrade transfected mHTT in Neuro-2a cells and endogenous mHTT aggregates and intranuclear inclusions in both fibroblasts from HD patients and neurons derived from induced pluripotent stem cells from patients. Our data showed that Gedunin treatment degraded transfected mHTT in Neuro-2a cells, endogenous mHTT aggregates and intranuclear inclusions in fibroblasts from HD patients, and in neurons derived from induced pluripotent stem cells from patients in a dose- and time-dependent manner, and its activity depended on the proteasomal pathway rather than the autophagy route. These findings also showed that although Gedunin degraded abnormal mHTT aggregates and intranuclear inclusions in cells from HD patient, it did not affect normal cells, thus providing a new perspective for using Gedunin to treat HD.
