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

Nature Neuroscience volume 13, pages 567–576 (2010)Cite this article

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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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Figure 1: Autophagic activity is reduced in HD cells.
Figure 2: Formation and clearance of autophagic vacuoles is normal in HD cells.
Figure 3: Abnormalities in autophagic vacuoles in different HD cell types.
Figure 4: Altered composition of autophagy-related compartments in HD cells.
Figure 5: Altered properties of autophagy-related compartments in HD cells.
Figure 6: Distribution of htt and p62 in autophagic vacuoles.
Figure 7: Consequences of altered recognition of autophagic cargo in HD on cellular lipid content.
Figure 8: Altered mitochondrial turnover in 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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Author notes

  1. Marta Martinez-Vicente & Zsolt Talloczy

    Present address: Present addresses: Institute of Neuropathology, IDIBELL–Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain (M.M.-Z.) and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA (Z.T.).,

  2. Marta Martinez-Vicente, Zsolt Talloczy and Esther Wong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA

    Marta Martinez-Vicente, Esther Wong, Hiroshi Koga, Susmita Kaushik, Esperanza Arias & Ana Maria Cuervo

  2. Departments of Neurology, Psychiatry, Pharmacology, Columbia University Medical School, New York, New York, USA

    Zsolt Talloczy, Guomei Tang, Rosa de Vries, Spike Harris & David Sulzer

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Contributions

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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Correspondence to David Sulzer or Ana Maria Cuervo.

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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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