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

Abstract

Continuous turnover of intracellular components by autophagy is necessary to preserve cellular homeostasis in all tissues. Alterations in macroautophagy, main 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 huntingtin protein. However, the precise mechanism behind macroautophagy malfunctioning in HD is poorly understood. In this work, using cellular and mouse models of HD and cells from HD patients, 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.