Abstract
Autophagy is a conserved lysosomal protein degradation pathway whose precise roles in age-dependent neurodegenerative diseases remain largely unknown. Here we show that the autophagy inhibitor 3-methyladenine delays neuronal cell loss caused by dysfunctional endosomal sorting complex required for transport III (ESCRT-III), either through loss of its essential component mSnf7-2 or ectopic expression of the disease protein CHMP2B(Intron5), which is associated with frontotemporal dementia linked to chromosome 3. Neuronal loss was also delayed by reduced activity of the autophagy genes atg5 and atg7. However, the endosomal accumulation of ubiquitinated proteins induced by dysfunctional ESCRT-III was not significantly affected, further confirming the essential contribution of dysregulated autophagy pathway in neurodegeneration. These findings show that autophagic stress by excess accumulation of autophagosomes is detrimental to neuronal survival under certain neurodegenerative conditions.
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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Adenine / analogs & derivatives
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Adenine / pharmacology
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Analysis of Variance
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Animals
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Autophagy / drug effects
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Autophagy / genetics
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Autophagy / physiology*
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Autophagy-Related Protein 5
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Autophagy-Related Protein 7
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cells, Cultured
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Cerebral Cortex / cytology
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Embryo, Mammalian
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Endosomal Sorting Complexes Required for Transport
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Green Fluorescent Proteins / genetics
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Humans
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Mice
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Mice, Knockout
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Microscopy, Electron, Transmission / methods
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Microtubule-Associated Proteins / deficiency
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mutation / genetics
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / drug effects
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Neurons / metabolism*
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Neurons / ultrastructure
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Propidium
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Rats
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Rats, Sprague-Dawley
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Time Factors
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Transfection / methods
Substances
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Atg5 protein, mouse
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Atg7 protein, mouse
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Autophagy-Related Protein 5
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CHMP2B protein, human
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CHMP4B protein, human
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Carrier Proteins
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Endosomal Sorting Complexes Required for Transport
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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RNA, Small Interfering
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Green Fluorescent Proteins
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Propidium
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3-methyladenine
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Autophagy-Related Protein 7
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Adenine