期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 28, 期 1, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.115175
关键词
Protein knockdown; Polyglutamine diseases
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Society for the Promotion of Science (KAKENHI) [17H03996, 17K19476]
- Grants-in-Aid for Scientific Research [17H03996, 17K19476] Funding Source: KAKEN
Polyglutamine diseases are a class of neurodegenerative diseases associated with the accumulation of aggregated mutant proteins. We previously developed a class of degradation-inducing agents targeting the beta-sheet-rich structure typical of such aggregates, and we showed that these agents dose-, time-, and proteasome-dependently decrease the intracellular level of mutant huntingtin with an extended polyglutamine tract, which correlates well with the severity of Huntington's disease. Here, we demonstrate that the same agents also deplete other polyglutamine disease-related proteins: mutant ataxin-3 and ataxin-7 in cells from spino-cerebellar ataxia patients, and mutant atrophin-1 in cells from dentatorubral-pallidoluysian atrophy patients. Targeting cross-beta-sheet structure could be an effective design strategy to develop therapeutic agents for multiple neurodegenerative diseases.
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