The many faces of autophagy dysfunction in Huntington's disease: from mechanism to therapy.

Journal Article (Journal Article;Review)

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.

Full Text

Duke Authors

Cited Authors

  • Cortes, CJ; La Spada, AR

Published Date

  • July 2014

Published In

Volume / Issue

  • 19 / 7

Start / End Page

  • 963 - 971

PubMed ID

  • 24632005

Pubmed Central ID

  • 24632005

Electronic International Standard Serial Number (EISSN)

  • 1878-5832

Digital Object Identifier (DOI)

  • 10.1016/j.drudis.2014.02.014


  • eng

Conference Location

  • England