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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Acknowledgements
We thank R. Singh and B. Patel for technical assistance. Mouse fibroblasts expressing 146Q-htt exon 1 and human lymphoblasts from unaffected controls and individuals with HD were gifts from N. Wexler (Hereditary Disease Foundation), M. Andresen (Massachusetts Institute of Technology) and J. Gusella (Massachusetts General Hospital). The antibodies to mannose-6-phosphate receptor and Rab5 were a gift from A. Wolkoff (Albert Einstein College of Medicine). This work was supported by a Huntington Disease Society of America grant (D.S., A.M.C.); US National Institutes of Health National Institute on Aging grants AG021904, AG031782, DK041918 (A.M.C.) and National Institute of Neurological Disorders and Stroke Udall Center of Excellence grant (D.S.); and the Glenn Foundation (A.M.C.), and Picower and Simons foundation (D.S.). E.W. is supported by the Hereditary Disease Foundation. E.A. is supported by a Fulbright fellowship. S.K. is supported by US National Institutes of Health National Institute on Aging grant T32AG023475.
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M.M.-V., Z.T. and E.W. performed the experiments that constitute the main body of this work; R.d.V., H.K., S.K., E.A. and G.T. completed the rest of the experiments; S.H. analyzed the electron micrographs of lymphoblasts; A.M.C. and D.S. designed the study and wrote the paper.
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Martinez-Vicente, M., Talloczy, Z., Wong, E. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat Neurosci 13, 567–576 (2010). https://doi.org/10.1038/nn.2528
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DOI: https://doi.org/10.1038/nn.2528
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