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The Journal of Neuroscience, July 1, 2009, 29(26):8506-8511; doi:10.1523/JNEUROSCI.0924-09.2009

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

Jin-A Lee and Fen-Biao Gao

Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, California 94158

Correspondence should be addressed to Fen-Biao Gao, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: fgao{at}gladstone.ucsf.edu

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.

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Received Feb. 23, 2009; revised May 12, 2009; accepted May 26, 2009.

Correspondence should be addressed to Fen-Biao Gao, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: fgao{at}gladstone.ucsf.edu

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