lunes, 12 de abril de 2010

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


Nature Neuroscience | Article

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
Affiliations Contributions Corresponding authors Journal name:
Nature Neuroscience
Year published:
(2010)
DOI:
doi:10.1038/nn.2528
Received 02 December 2009 Accepted 09 March 2010 Published online 11 April 2010


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.

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http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.2528.html

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