Autophagy defects contribute to neurodegeneration induced by dysfunctional ESCRT-III

 Abstract

The endosomal sorting complex required for transport (ESCRT) machinery is involved in multiple cellular processes, including autophagy (macroautophagy). Autophagy is an important intracellular pathway that involves the formation and maturation of autophagosomes and their fusion with lysosomes for bulk degradation of cytoplasmic contents and organelles. In flies and cultured mammalian cells, autophagosomes accumulate when ESCRT-III is rendered dysfunctional by reduced activity of its subunits or by ectopic expression of mutant CHMP2B associated with frontotemporal dementia linked to chromosome 3 (FTD3). Compromised ESCRT-III function results in eventual neuronal cell loss; however, the mechanism of this form of neurodegeneration is largely unknown. Recently, we found that inhibiting autophagy induction in cultured cortical neurons, either by small-molecule inhibitors of phosphatidylinositol 3-kinases (PtdIns3K) or by loss of atg5 or atg7 activity, delays but does not completely suppress neuronal cell loss caused by dysfunctional ESCRT-III. These findings indicate that excess accumulation of autophagosomes is detrimental to neuronal survival, and dysfunctional ESCRT-III appears to cause neurodegeneration through multiple mechanisms.

 Related Article:

JA Lee, FB Gao. Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia. J Neurosci 2009; 29: 8506- 11.
PMID: 20926670 DOI: 10.1523/JNEUROSCI.09

Full Text Options
Article
Metrics
 Share
 Full Text
 Info
Pages
1070 - 1072
doi
10.4161/auto.5.7.9823
Type
Autophagic Punctum
 Metrics
 Cite This Article
 Permissions
 Permissions
 Reprints
Autophagy defects contribute to neurodegeneration induced by dysfunctional ESCRT-III