期刊
DRUG DISCOVERY TODAY
卷 19, 期 7, 页码 963-971出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.drudis.2014.02.014
关键词
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资金
- National Institutes of Health [R01 AG033082, R01 NS065874]
- Muscular Dystrophy Association (Basic Research Award) [DG 273985]
- Hereditary Disease Foundation
- Child Health and Development Institute
Autophagy is the cellular process by which proteins, macromolecules, and organelles are targeted to and degraded by the lysosome. Given that neurodegenerative diseases involve the production of misfolded proteins that cannot be degraded by the protein quality-control systems of the cell, the autophagy pathway is now the focus of intense scrutiny, because autophagy is primarily responsible for maintaining normal cellular proteostasis in the central nervous system (CNS). Huntington's disease (HD) is an inherited CAG-polyglutamine repeat disorder, resulting from the production and accumulation of misfolded huntingtin (Htt) protein. HD shares key features with common neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) and, thus, belongs to a large class of disorders known as neurodegenerative proteinopathies. Multiple independent lines of research have documented alterations in autophagy function in HD, and numerous studies have demonstrated a potential role for autophagy modulation as a therapeutic intervention. In this review, we consider the evidence for autophagy dysfunction in HD, and delineate different targets and mechanistic pathways that might account for the autophagy abnormalities detected in HD. We assess the utility of autophagy modulation as a treatment modality in HD, and suggest guidelines and caveats for future therapy development directed at the autophagy pathway in HD and related disorders.
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