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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / physiology
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Autophagy / drug effects
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Autophagy / physiology*
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Cells, Cultured
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Huntington Disease / genetics
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Huntington Disease / pathology*
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Huntington Disease / physiopathology*
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Immunosuppressive Agents / pharmacology
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Lysosomes / drug effects
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Lysosomes / metabolism
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Lysosomes / ultrastructure
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Mice
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Mice, Transgenic
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Microscopy, Electron, Transmission / methods
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Microtubule-Associated Proteins / metabolism
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Mitochondria / pathology
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Mitochondria / ultrastructure
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects
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Neurons / ultrastructure
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Peptides / genetics
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Serotonin Plasma Membrane Transport Proteins / genetics
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Serum / metabolism
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Sirolimus / pharmacology
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Subcellular Fractions / metabolism
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Subcellular Fractions / pathology
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Subcellular Fractions / ultrastructure
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Thapsigargin / pharmacology
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Time Factors
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Vinca Alkaloids / metabolism
Substances
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Enzyme Inhibitors
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Immunosuppressive Agents
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MAP1LC3A protein, human
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MAP2 protein, human
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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Peptides
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Serotonin Plasma Membrane Transport Proteins
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Slc6a4 protein, mouse
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Vinca Alkaloids
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polyglutamine
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Thapsigargin
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eburnamonine
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Sirolimus