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.

Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6

“…The accumulation of autophagosomes has been observed in several neurodegenerative diseases, such as HD (14,15), and in multiple sulfatase deficiency, a lysosomal storage disease in which an impairment of the autophagic flux has been demonstrated (16,17). We could, however, hardly detect autophagic vacuoles in the cytoplasm of the MPI 118Q/118Q PCs by TEM.…”

Autophagy at the crossroads of catabolism and anabolism

“…Macrolipophagy is not limited to hepatocytes; it also occurs in fibroblasts, endothelial cells, lymphoblasts, dendritic cells, glial cells and neurons, suggesting that autophagic lipid degradation is important in diverse cell types [65][66][67] . Moreover, macrolipophagy has been reported in yeast, in which the degradation of lipid droplets is thought to support cell viability under carbon starvation.…”

Chaperone-mediated autophagy: roles in disease and aging

“…For example, recent studies have revealed that constitutive upregulation of CMA [77] compensates for the dual failure of macroautophagy [78,79] and UPS [80] seen in mouse models of Huntington's disease (HD). Activation of CMA in HD is achieved through both enhanced transcription and increased stability of LAMP-2A in the affected cells [77].…”