Inhibition of Autophagy Induction Delays Neuronal Cell Loss Caused by Dysfunctional ESCRT-III in Frontotemporal Dementia

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 tr...

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Bibliographic Details
Published in:The Journal of neuroscience 2009-07, Vol.29 (26), p.8506-8511
Main Authors: Lee, Jin-A, Gao, Fen-Biao
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - pharmacology
Analysis of Variance
Animals
Autophagy - drug effects
Autophagy - genetics
Autophagy - physiology
Autophagy-Related Protein 5
Autophagy-Related Protein 7
Brief Communications
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cells, Cultured
Cerebral Cortex - cytology
Embryo, Mammalian
Endosomal Sorting Complexes Required for Transport
Green Fluorescent Proteins - genetics
Humans
Mice
Mice, Knockout
Microscopy, Electron, Transmission - methods
Microtubule-Associated Proteins - deficiency
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Mutation - genetics
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurons - drug effects
Neurons - metabolism
Neurons - ultrastructure
Propidium
Rats
Rats, Sprague-Dawley
RNA, Small Interfering - genetics
RNA, Small Interfering - pharmacology
Time Factors
Transfection - methods
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0924-09.2009