Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease

Marta Martinez-Vicente, Zsolt Talloczy, Esther Wong, Guomei Tang, Hiroshi Koga, Susmita Kaushik, Rosa De Vries, Esperanza Arias, Spike Harris, David Sulzer, Ana Maria Cuervo

Research output: Contribution to journalArticle

459 Scopus citations

Abstract

Continuous turnover of intracellular components by autophagy is necessary to preserve cellular homeostasis in all tissues. Alterations in macroautophagy, the main process responsible for bulk autophagic degradation, have been proposed to contribute to pathogenesis in Huntington's disease (HD), a genetic neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin protein. However, the precise mechanism behind macroautophagy malfunction in HD is poorly understood. In this work, using cellular and mouse models of HD and cells from humans with HD, we have identified a primary defect in the ability of autophagic vacuoles to recognize cytosolic cargo in HD cells. Autophagic vacuoles form at normal or even enhanced rates in HD cells and are adequately eliminated by lysosomes, but they fail to efficiently trap cytosolic cargo in their lumen. We propose that inefficient engulfment of cytosolic components by autophagosomes is responsible for their slower turnover, functional decay and accumulation inside HD cells.

Original languageEnglish (US)
Pages (from-to)567-576
Number of pages10
JournalNature Neuroscience
Volume13
Issue number5
DOIs
StatePublished - May 1 2010

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., De Vries, R., Arias, E., Harris, S., Sulzer, D., & Cuervo, A. M. (2010). Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nature Neuroscience, 13(5), 567-576. https://doi.org/10.1038/nn.2528